Written by Dennis K. Chernin, MD, MPH | 08 June 2010

Best Evidence Interview: Using Red Yeast Rice to Lower Cholesterol in Patients Intolerant to Statins

Expert Interview With David J. Becker, MD

Halbert SC, French B, Gordon RY, et al. Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance. Am J Cardiol. 2010;105:198-204. Epub 2009 Nov 26.

This study was selected as the subject of this interview because of its high ranking in Medscape Best Evidence, which uses the McMaster Online Rating of Evidence System. Of a possible top score of 7, clinicians who used this system ranked this study as 6 for relevance and 6 for newsworthiness.

About the Interviewee: David J. Becker, MD

David J. Becker, MD, is a Cardiologist at Chestnut Hill Cardiology, Ltd., Chestnut Hill Hospital/Abington Memorial Hospital, University of Pennsylvania Health System, Philadelphia, Pennsylvania. He joined Chestnut Hill Cardiology in 1990. He is board certified in both internal medicine and cardiovascular diseases, and is a fellow in the American College of Cardiology. His clinical interests include preventive cardiology and alternative cholesterol treatments. Dr. Becker has developed a cardiovascular health program known as "Change of Heart," which began at Chestnut Hill Hospital in 1993. The 10-week program employs a holistic approach, including a modified Mediterranean diet, consistent aerobic exercise, and a variety of stress management techniques designed to reverse heart disease and improve quality of life. The program enables many participants to lower their cholesterol and blood pressure, lose weight, avoid surgery, reduce the negative effects of stress, and reduce their medications. Dr. Becker, along with his colleague Dr. Ram Gordon, has published several studies demonstrating the beneficial effects of therapeutic lifestyle changes and supplements to lower cholesterol levels.

Introduction to the Interview

Red yeast rice is a dietary supplement made by fermenting rice with the yeast Monascus purpureus that has been used for centuries in Chinese traditional medicine. In the late 1990s, studies in China and the United States reported that red yeast rice could significantly reduce low-density lipoprotein cholesterol (LDL-C) and total cholesterol in humans,^[1-4] and it was suggested that red yeast rice might represent a novel alternative approach to achieving normal cholesterol levels. Chemical analyses of the fermented product revealed that it contains a number of naturally occurring 5-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, monacolins.^[5-7] One of these, the major ingredient, is monacolin K, also known as mevinolin or lovastatin. Lovastatin was the first statin approved in the United States, where it is now available as Mevacor® (Merck & Co., Inc.; Whitehouse Station, NJ), Altoprev® (Watson Laboratories; Ft. Lauderdale, Fla), and Altocor™ (Andrx Corporation; Davie, Fla). Products containing lovastatin are considered "new drugs" and may not be legally marketed without approval by the US Food and Drug Administration (FDA). A number of red yeast rice products are currently marketed in capsule formulation as dietary supplements, and as such must conform to the Dietary Supplement Health and Education Act (DSHEA). In 2007 the FDA discovered that a number of red yeast rice supplements being promoted for their cholesterol-lowering effects contained monacolin K/lovastatin and took steps to have them removed them from the market.^[8] More recent analyses of other red yeast rice formulations currently available, however, have shown that they also contain varying amounts of monacolin K/lovastatin.^[9,10]

Dr. Becker and colleagues have studied the administration of red yeast rice along with a therapeutic lifestyle change program in people unwilling or unable to take statins.^[11,12] Their latest study, funded by an unrestricted grant from the Commonwealth of Pennsylvania, was the first randomized, double-blind trial to compare the tolerability of red yeast rice with that of a statin drug in a population with statin-associated myalgia (ie, muscle pain, stiffness or cramps without neurologic signs).^[13] A total of 43 adults with dyslipidemia and a history of statin discontinuation due to myalgia were recruited from preventive cardiology clinics in Pennsylvania. All patients were randomly assigned to either red yeast rice 4800 mg daily, taken as 4 x 600-mg capsules twice daily (Naturals™ Red Yeast Rice, Sylvan Bioproducts, Inc.; Kittanning, Pa) or pravastatin 20 mg twice daily. All participants were concomitantly enrolled in a therapeutic lifestyle change program. After 12 weeks, both treatments were associated with a low incidence of treatment discontinuation due to myalgia, no evidence of muscle weakness, and a similar level of LDL-C reduction. Mean LDL-C level decreased 30% in the red yeast rice group and 27% in the pravastatin group. Withdrawal due to myalgia was 5% (1 of 21) in the red yeast rice group and 9% (2 of 22) in the pravastatin group (P = .99). Isometric hip flexor muscle strength did not differ between the 2 groups at week 4 (P = .61), week 8 (P = .81), or week 12 (P = .82). In an exploratory analysis, the rate of recurrent myalgia reported as persistent and generalized was 14% lower in the red yeast rice group vs the pravastatin group. In their report, Dr. Becker and colleagues cautioned that their results could not be extrapolated to other red yeast rice formulations and that no inference about the long-term effects of this product on cardiovascular morbidity or mortality could be drawn from this study.

Dr. Becker spoke with Linda Brookes, MSc, for Medscape Cardiology, to discuss some of the implications of the study's findings for Medscape's readers.

The Interview

Medscape: How did you first become interested in the use of red yeast rice to lower LDL-C?

Dr. Becker: My interest goes back to the lifestyle program that I have been running for 16 years called "Change of Heart." This involves a commitment to attempting fairly aggressive lifestyle changes. People who were following the program had a near-uniform desire to try to come off statins. When they would do that, however, I would find that their LDL-C levels would drop by only about 8%-10%, which was not enough to achieve their target LDL-C goal. About 10 years ago, several patients coming into my office told me that they had stopped their statins, yet had wonderful cholesterol numbers. I asked them what they were doing, and they mentioned that they were taking a substance called red yeast rice. I had never heard of it at the time., but more patients began using it, and I became interested in developing a study to see whether it actually worked. I was able to secure a grant from the Commonwealth of Pennsylvania to do an initial study leading to the subsequent trials that we have done.^[11-13]

Medscape: Your 2 latest studies^[12,13] were carried out in patients who were statin intolerant. Had they all experienced adverse effects while on a statin, or were there other reasons why they discontinued statins, such as cost or failure to adhere to the regimen?

Dr. Becker: All the patients in these studies had been put on statins by their physicians and had stopped them because of complaints of muscle aches. When the medication was withdrawn, the myalgia resolved. Many of these patients were rechallenged, and most tried at least 2 different statins and stopped them, in each case because of recurrent muscle aches.

Medscape: Isn't it difficult to confirm that myalgia is statin related?

Dr. Becker: This is a big problem. Physicians prefer to order a test to discover whether something is a problem or not, and there is no such test for this condition. If someone has myopathy or even, much worse, rhabdomyolysis, which is frank muscle breakdown, then this can be confirmed by an elevated serum level of creatinine phosphokinase (CPK). However, myalgia is much more prevalent and much more difficult to get a handle on. In the large randomized trials involving statins, only 1%-2% of people had myalgias that led to their stopping the drug, whereas in clinical practice, estimates range from 10% to 20%.

Medscape: So myalgias were underreported in the clinical trials of statins and are probably overreported in daily practice?

Dr. Becker: Yes, they are likely underreported in clinical trials. However, many myalgias in clinical practice may not be statin related. Some patients may take 1 or 2 pills, have some discomfort, and stop their drug. This is unlikely to be statin intolerance, and probably overinflates the reports of patients who stop their medication in daily practice. However, we did carefully screen patients for our trials to select ones who had experienced statin-associated myalgia, and not those who stopped therapy for other reasons.

Medscape: Among the patients entered into this study, 14% of each treatment group had a history of coronary artery disease (CAD). Wouldn't these patients be at higher cardiovascular risk than the others and need more aggressive treatment to reach their LDL-C goal, according to guidelines?^[14]

Dr. Becker: The study was primarily for primary prevention patients, but there were a couple of people who had noncritical coronary disease and were not taking any statin at all due to myalgias. If a patient was tolerating a statin and had known CAD, this was an absolute exclusion criterion for our study. I would not recommend using red yeast rice in any patient with CAD who is successfully tolerating a statin.

Medscape: Your study did not show any difference in benefit or side effects between the red yeast rice and pravastatin groups.

Dr. Becker: That study had several limiting factors. It involved a very small number of patients, and although we could not demonstrate a difference between pravastatin and red yeast rice, the bottom line was that they were both extremely well tolerated. These were all people who had demonstrated statin intolerance and they all did surprisingly well, and there were so few side effects that we could not show a difference between pravastatin and the red yeast rice.

Medscape: I believe that, although there have not been any comparative trials, pravastatin is known to be one of the statins least associated with myopathy.

Dr. Becker: That is why we chose it. The 2 statins that have been demonstrated in trials to have the least myalgia are pravastatin and fluvastatin.

Medscape: Why did you choose the particular red yeast rice preparation that you used in the trial?

Dr. Becker: In our first study, we used a brand of Chinese red yeast rice that had higher monacolin content (Res-Q® LDL-X 600-mg capsules, N3 Oceanic, Inc.; Palm, Pa).^[11] For the last 2 trials, we used Naturals 600-mg capsules (Sylvan Bioproducts, Inc.).^[12,13] The reason that we chose that brand was that it came from a reliable supplier, and we have had the formulation analyzed in the lab several times.^[9,15] I would like to emphasize that I have no affiliation with Sylvan Bioproducts, and I do not endorse that particular product.

Medscape: What appears somewhat confusing is that in your trial, red yeast rice appears to have lowered LDL-C because it contained monacolin K/lovastatin (1.245 mg/capsule). With a daily dose of 4800 mg of red yeast rice, patients were getting about 8 mg/day of lovastatin. Therefore, why not just give patients a low dose of lovastatin, as others have suggested?^[16-18]

Dr. Becker: If you were to give a patient half of a 10-mg tablet of lovastatin, the LDL-C lowering effect would not be very impressive. However, with red yeast rice this low dose of lovastatin equivalent has been shown to produce a 22%-28% decrease in LDL-C, and in this last study, it produced a 30% decrease in LDL-C. There is a disconnect there, and our theory is that it is related to the other monacolins in red yeast rice, which may potentiate the effects of monacolin K.^[12,19,20]

Medscape: Could it also be related to the effects of phytosterols present in red yeast rice? Many phytosterols have been shown to lower LDL-C.^[21] Are there also isoflavones and monounsaturated fatty acids in red rice yeast that might have an LDL-C lowering effect?

Dr. Becker: Although there are small amounts of both phytosterols and monounsaturated fatty acids in red yeast rice, our theory is that it is more likely to be the effect of the different monacolins. The amount of phytosterols in red yeast rice is trivial. Isoflavones and monounsaturated fatty acids are also present in small amounts that do not have much lipid-lowering properties. Of interest, in our next trial with red yeast rice we are combining it with phytosterols.^[22] We are halfway through that trial right now, which will examine the lipid-lowering effects of red yeast rice with and without a phytosterol.

Medscape: What kind of supplement are you using for the phytosterol?

Dr. Becker: It is a plant-based, soy-based material. Phytosterols should be taken before a meal because the phytosterol displaces cholesterol in the micelles in the intestinal lumen, inhibiting cholesterol absorption. The appealing aspect of this is that there is a lack of side effects because nothing is absorbed in the intestine. For our next study, we purchased phytosterol pills and matching placebos from the same company. To date we have randomly sampled almost 200 people, half of whom are doing our lifestyle program and half are not. Everyone is taking red yeast rice 3 x 600-mg capsules twice daily, and half have been randomly sampled to take phytosterol 2 x 450-mg tablets twice daily with food, and half to take a placebo. It will hopefully show some interesting results.

Medscape: When can we expect to see the results of this study?

Dr. Becker: Our trial will be completed in November this year. We have 3-month data that look encouraging, but they have not been tabulated.

Medscape: Obviously, people in clinical trials that involve lifestyle changes are more motivated to follow them than they are in real life. Could this account for at least part of the improvement in your studies?

Dr. Becker: People who change their lifestyle are likely to be more motivated, and I believe that this may actually help reduce the incidence of mylagias. Positive attitudes toward exercising, less depression, and the group setting seem to make an important difference. However, when participants in the lifestyle program took red yeast rice vs placebo, the red yeast rice group did significantly better.

Medscape: Does red yeast rice have any other effect on lipids aside from lowering LDL-C?

Dr. Becker: In our latest study, the only statistically significant effects were the LDL-C and total cholesterol values. High-density lipoprotein cholesterol (HDL-C) levels did not change significantly, and the effect on triglycerides was of borderline but not statistical significance.

Medscape: So red yeast rice really is a statin alternative; it is not going to be a substitute for a fibrate or niacin?

Dr. Becker: Other studies have demonstrated triglyceride lowering with red yeast rice,^[2,23-25] but HDL-C has not been shown to be significantly affected. So I would agree that I do not believe that red yeast rice is as effective in raising HDL-C and lowering triglycerides as a drug, such as niacin. The key point to focus on is that red yeast rice has a mix of about 12 different monacolins that may have cholesterol-lowering effects, only one of which, monacolin K, is lovastatin. The other monacolins seem to have cholesterol-lowering effects that are not yet well characterized, but they may work similarly to a statin on the HMG-CoA [3-hydroxy-3-methylglutaryl coenzyme A] reductase inhibitor enzymes. I personally believe that the isoflavones, free fatty acids, and phytosterols are a bit of a distraction because by weight they are a tiny amount of this fermentation product. However, red yeast rice is a fermentation product, so, by definition, it is going to be difficult to characterize some of the metabolites. Our theory is that there may be something about this combination of monacolins that has additional lipid-lowering abilities but does not trigger that myalgia response in humans, and it seems to be extremely well tolerated. Therefore, it may be a simple case of going back centuries to find a product that has been around that is better tolerated than the pharmaceutically produced drug.

Medscape: I believe that there have been some reports of statinlike adverse effects with red yeast rice?

Dr. Becker: There have been rare cases of elevated CPK,^[26-28] and 1 reported case in the literature of rhabdomyolysis in a renal transplant patient.^[29]

Medscape: A nonstatin drug that has been promoted as a cholesterol-lowering agent is the intestinal cholesterol absorption inhibitor ezetimibe (Zetia®; Merck/Schering-Plough Pharmaceuticals, North Wales, Pa). Wouldn't that be preferable to using a supplement? Apparently, ezetimibe is not associated with myalgia when administered alone?^[30]

Dr. Becker: I do not believe that ezetimibe, which only lowers LDL-C by about 18%-19%, has much of a role as a stand-alone drug. Ezetimibe may be associated with myalgia, although we do not understand the mechanism.

Medscape: Although ezetimibe was shown to lower LDL-C, in imaging studies it did not show any effect on atherosclerosis,^[31-33] and we will not know anything about its effects on outcomes until the results of the Improved Reduction of Outcomes: VYTORIN Efficacy International Trial (IMPROVE-IT) come out around 2015.^[34] It was said that ezetimibe should not have been approved by the FDA because benefit for it had not been shown in a large outcomes trial.^[35] So how can red yeast rice be accepted as an effective treatment for lowering LDL-C in primary prevention without an outcomes trial, such as the West of Scotland Coronary Prevention Study (WOSCOPS)^[36] and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS),^[37] which showed that statins prevented cardiovascular events?

Dr. Becker: Although a morbidity and mortality trial would be useful, I do not think that it is going to happen. Red yeast rice is an over-the-counter supplement, and such a trial would be enormously expensive and take several years. Of interest, the major concern that I hear from cardiologists and internists about red yeast rice is that it is very difficult to recommend because there is such variability in the supply.

Medscape: Last year at the annual meeting of the American College of Cardiology, you presented data from analyses of 12 commercially available red yeast rice formulations that showed a wide range of monacolin K content in each sample, although each contained a significant amount of content of monacolins.^[9]

Dr. Becker: Yes; the variability of monacolin content is a real concern. These data will hopefully be published in an upcoming study later this year.

Medscape: The only other analysis that I have seen of products sold in the United States is a report byConsumerLab.com,^[10] which is not in the literature. It did not include the red yeast rice supplement that you used in your last study.

Dr. Becker: Dr. Gordon and I are collaborating with the people at ConsumerLab.com, and these data will be included in our upcoming study.

Medscape: How high does the amount of lovastatin in red yeast rice get in these supplements?

Dr. Becker: There was one in the ConsumerLab.com analysis that had a very high amount of monacolin K -- 10.6 mg/capsule -- suggesting that it might have been spiked with lovastatin. There is really nothing to stop manufacturers doing this.

Medscape: In 2007, the FDA issued warning letters to some manufacturers because their red yeast rice products contained lovastatin.^[8]

Dr. Becker: They all do.

Medscape: However, the FDA says that red yeast rice containing lovastatin cannot be sold because it contains an unapproved drug.

Dr. Becker: The current regulatory status is, to say the least, murky, and the FDA has said that these products are illegal.

Medscape: There appears to be no control over dietary supplements. Should they not have to meet standards?

Dr. Becker: I think that the variability of red yeast rice supply on the market calls for more regulation. I would hope that more regulation would not result in all of these products being off the market, because they do work.

Medscape: In another recently published study by US researchers,^[38] statin-intolerant patients took red yeast rice supplements that they chose and purchased themselves, and they took a single daily dose of only 1200 mg at bedtime. Nonetheless, there were significant decreases of 13% in LDL-C and 19% in total cholesterol.

Dr. Becker: I was surprised at how effective red yeast rice was in that study. My concern with red yeast rice is that with people choosing their own, they may know what they are getting.

Medscape: The dose in that study seemed to be quite low.

Dr. Becker: Yes, 1200/mg is low.

Medscape: Do you think that all of these studies might encourage people who believe that anything described as "natural" or "organic" is better than an approved prescription drug?

Dr. Becker: Several years ago, after an article appeared in the Philadelphia Inquirer about our first study,^[39] I answered questions in a forum, and the number one question was: "Dr. Becker, I have stopped my atorvastatin and am now taking red yeast rice; what dose do you recommend?" This was disconcerting, and I hope that this research does not encourage people who feel well on established therapy to stop it. Something natural or organic is not inherently better, and as we have discussed, may have drawbacks, such as lack of efficacy. Patients can hurt themselves if they stop a medication that is prescribed and switch to a supplement. Red yeast rice will have a role limited to patients with statin intolerance, or lower-risk patients for primary prevention until there are more data.

Medscape: Therefore, in an ideal world, how would your research continue in the future?

Dr. Becker: In an ideal world, I think there would be a product that eventually was approved by the FDA as a traditional drug. I think that that is the way it could have the most impact on people, because as long as it remains unregulated and there is no quality control, it is very difficult for physicians to recommend its use. Thus, one approach would be for the FDA to work with some of the companies that currently produce red yeast rice supplements and work on a tract to approve it as a traditional medication.

Medscape: Would that mean having to do an outcomes trial, though?

Dr. Becker: It might not need an outcomes trial, but it would need to be a much more powerful trial than the ones we have done. Traditionally, cholesterol-lowering medication is judged by its LDL-C-lowering effect, but as you pointed out, after the ezetimibe problem, that might change.