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Identity of statins in RYR
Submit responseIn the article “Red Yeast Rice for Dyslipidemia in Statin-Intolerant Patients” by Becker and colleagues in the June issue of the Annals, the authors suggest that the monacolins present, other than monacolin K (lovastatin), might inhibit HMG-CoA reductase, when in fact the most- prevalent monacolins in these samples of red rice yeast (RYR) are well- known to do so.
For example, the analysis of RYR capsules in the current study shows the presence of Monacolin KA, which is mevinolinic acid, the open-chain hydroxyacid form of Monacolin K and the active form of the drug in vivo(1). Additionally, dihydromonacolin K, or dihydromevinolin, is essentially equipotent to lovastatin(2). Thus, the overall dose of statins in this study was equivalent to at least 11.0 mg of lovastatin. In the authors’ prior publication on higher-potency red yeast rice versus statin treatment(3), similar consideration of the chemical analysis would reveal that the patients in that study treated with RYR were receiving the equivalent of 30 mg per day of lovastatin.
In the recent Annals paper, the authors propose a future study to compare the incidence of myalgias in patients treated with RYR versus statin therapy. If such a study is performed, it is incumbent upon the authors to correctly account for the quantities and relative potencies of the naturally-occurring statins in RYR.
References:
1. Alberts et al. Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci USA 1980;77:3957-3961
2. Albers-Schonberg, et al. Dihydromevinolin, a potent hypocholesterolemic metabolite produced by Aspergillus terreus. The Journal of antibiotics 1981; 34(5):507-12
3. David J. Becker, MD, et al. Simvastatin vs Therapeutic Lifestyle Changes and Supplements: Randomized Primary Prevention Trial. Mayo Clinic Proc. July 2008;83(7):758-764
Conflict of Interest:
None declared
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Red yeast rice in statin-intolerant patients
Submit responseBecker et al’s study employed 6 capsules of red yeast rice that contain a total of 6X2.16=12.96 milligrams of possible HMG-Co A reductase inhibitors. This amount of statin like compounds is larger than the smallest denomination of lovastatin available in the market, i.e. 10 milligrams. The therapeutic effects of cholesterol lowering observed in the study could easily be explained by the amount of statins or statin like substances in red yeast rice. Lower dose of statins might also explain the low incidence of statin induced side effects since statin induced side effects could be dose dpenedent(1,2). Employing a third arm in the study with a low dose statin and thus a three way comparison between red yeast rice, low dose statin and placebo might have provided more clues regarding the usefulness of red yeast rice in statin-intolerant patients.
Based on the data in the study, red yeast rice may be useful in statin-intolerant patients who are entirely against trying a low dose statin and want to use a “natural cure” for their hyperlipidemia.
References
1. Backes JM, Venero CV, Gibson CA, Ruisinger JF, Howard PA, Thompson PD, et al. Effectiveness and tolerability of every-other-day rosuvastatin dosing in patients with prior statin intolerance. Ann Pharmacother 2008;42:341-6.
2. Mackie BD, Satija S, Nell C, Miller J 3rd, Sperling LS. Monday, Wednesday, and Friday dosing of rosuvastatin in patients previously intolerant to statin therapy. Am J Cardiol2007;99:291
Conflict of Interest:
None declared
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Response from the authors
Submit responseDr. Kolpakchi nicely summarizes the regulatory history of red yeast rice (RYR), but does not focus on our major point. Namely, that regardless of their legal status, many RYR products are commercially available in this country and are currently consumed by patients. Therefore, well- designed trials evaluating RYR and other herbal supplements are not “immaterial,” but actually necessary to improve our knowledge about the efficacy and safety of these products that are already in use.
We agree with Le Couteur that the pharmokinetics of RYR are not well studied. The patients in our study took RYR with monacolin K (lovastatin) content equivalent to only 6 mg/day, much lower than the typical daily dosage of 40 mg used to achieve the LDL-cholesterol lowering seen in our study. We hypothesize that the 13 other monacolins present in RYR have additive lipid-lowering effects. He also questions whether the sweet smell associated with RYR may have adversely affected blinding. However, smell was not an issue in our study as effective encapsulation rendered our active product odorless. Furthermore there was no difference in appearance between RYR and placebo.
We completely agree with Vannacci that there are safety issues with taking RYR, especially when patients prefer taking a “natural” product because they perceive that it may be safer. We believe that larger and longer-term trials are required to adequately assess the safety of RYR in hyperlipidemic patients with and without a history of statin myalgias.
Presently, we agree that it is difficult to recommend RYR to patients because of the variability of active ingredients among different commercial preparations, lack of adequate regulation by the Food and Drug Administration, and inadequate screening for potential toxins. However, the fact remains that 19-50% of U.S adults use natural products(1,2) and many patients are taking RYR for dyslipidemia, often without the knowledge of their physician. It is likely that consumption of RYR by consumers will only increase, as several promising positive studies have been published in the past few years.(3-5) It would be irresponsible to ignore these facts. Instead, we should conduct well-designed, large, randomized trials to determine if herbal supplements (like RYR) are efficacious and safe. Eventually, this research may lead to better regulation of these products, so physicians can feel more confident about recommending them to their patients.
Finally, we would like to emphasize that a Therapeutic Lifestyle Program, like the one participants followed during this study, is a critical part of lipid-lowering therapy for any patient with hyperlipidemia.
REFERENCES
1. Qato DM, Alexander GC, Conti RM, Johnson M, Schumm P, Lindau ST. Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States. Jama. Dec 24 2008;300(24):2867- 2878.
2. Barnes PM, Powell-Griner E, McFann K, Nahin RL. Complementary and alternative medicine use among adults. Advance Data from Vital and Health Statistics, US Dept of Health and Human Services, Rockville, MD. 2004.
3. Becker DJ, Gordon RY, Morris PB, et al. Simvastatin vs therapeutic lifestyle changes and supplements: randomized primary prevention trial. Mayo Clin Proc. Jul 2008;83(7):758-764.
4. Huang CF, Li TC, Lin CC, Liu CS, Shih HC, Lai MM. Efficacy of Monascus purpureus Went rice on lowering lipid ratios in hypercholesterolemic patients. Eur J Cardiovasc Prev Rehabil. Jun 2007;14(3):438-440.
5. Lu Z, Kou W, Du B, et al. Effect of Xuezhikang, an extract from red yeast Chinese rice, on coronary events in a Chinese population with previous myocardial infarction. Am J Cardiol. Jun 15 2008;101(12):1689- 1693.
Conflict of Interest:
None declared
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Demystifying Red Yeast Rice
Submit responseIt is with great interest that we read the article “Red Yeast Rice for Dyslipidemia in Statin-Intolerant Patients” by Becker and colleagues in the June issue of the Annals. The history of the emergence of Red Yeast Rice (RYR) as a dietary supplement and cholesterol-lowering agent demonstrates why such supplements are currently classified as unapproved drugs under the Dietary Supplement Health and Education Act (1). RYR as a supplement did not exist until 1993. However, it has been used as food coloring and flavoring agent throughout the Orient for centuries and its medicinal use for indigestion, diarrhea and blood circulation is mentioned in ancient Chinese Pharmacopoeia. Originally, it was made by fermenting cooked white rice with Monascus purpureus in the open air. In November of 1978, Dr. Alberts (Merck, USA) isolated lovastatin from Aspergillus terreus. In February of 1979, Professor Endo (Tokyo Noko University, Japan) also isolated monakolin K, a lovastatin analogue, from a certain strain of Monascus purpureus. In 1987, FDA approved lovastatin (Merck) as the first cholesterol lowering drug (2). The first RYR supplement, Cholestin, was made by Pharmanex in 1993. It was advertised as a natural ancient Chinese remedy that lowers cholesterol. Trials showed its short-term effectiveness and safety (3). Subsequent FDA investigation demonstrated that Cholestin contained substantial quantities of lovastatin. This was attributed to the use of proprietary technology and of a particular strain of Monascus purpureus to ferment rice for manufacturing the supplement. When samples of traditional RYR from Chinese stores were tested, it was determined that most of them contained very little or no lovastatin (4). As a result, FDA declared Cholestin an unapproved drug rather than a supplement and banned it from the market in 2001 (1). In addition, statin-related toxicity reports from RYR supplements emerged (5). Although all RYR supplements containing lovastatin were withdrawn from the market by 2008, they are still available in other countries and via the Internet. In summary, RYR supplements containing lovastatin are considered unapproved drugs by FDA. Therefore, any trials utilizing them are immaterial and perpetuate their mystification.
References:
1. Dietary Supplement Health and Education Act of 1994. Public law 103- 417, 1994.
2. Akira Endo The origin of the statins. Atherosclerosis supplement 5(2004)125-130.
3. Current Therapeutic Research 1997; 58: 964-978; Am J Clin Nutr 1999; 69: 231-6.
4. US Department of Health and Human Services. Food and Drug Administration. Pharmanex, Inc, administrative proceeding. Public Docket No 97P-0441.
5. Transplantation 2002;74:1200-1, South Med J. 2003;96:1265-1267; Ann Intern Med. 2006;145:474-5; Am J.Med. 2007;120:e3-4. Br J Clin Pharmacol. 2008; 66:572-4; Ann Intern Med.2008; 149:516-7
Conflict of Interest:
None declared
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Red yeast rice: Beneficial systemic effects beyond hyperlipidemia
Submit responseTO THE EDITOR: I read with great interest the recent article by Becker et al in the June edition of the “Annals of internal medicine” (1). The authors have clearly shown that red yeast rice is effective as a treatment modality for dyslipidemia in statin intolerant patients. The findings of Becker et al are highly important as they highlight and add to the increasing evidence in support of red yeast rice as a treatment option in the management of other systemic pathologies besides hyperlipidemia.
For instance, red yeast rice has been shown to decrease tumor proliferation in certain androgen dependent tumors such as prostate carcinomas. (2) Monacolin K, a component of red yeast rice extracts also plays a similar role in attenuating tumor proliferation in colon malignancies (3).
Similarly, red yeast rice has a negative effect on growth and division in preadipocyte cells and thereby exerts a positive influence by decreasing weight gain (4). In fact, the CAD mortality is decreased by almost one third in populations using red yeast rice concoctions such as “xuezhikang” (5). Recent research also suggests that red yeast rice enhances new bone synthesis and thus has a pro- osteogenic effect especially during the healing process in bony defects in skeletal tissue.
The above examples clearly highlight the rapidly expanding role of red yeast rice as a natural treatment alternative in the management of systemic conditions and the need for further studies to fully elaborate its other beneficial effects.
REFERENCES
1. Becker DJ, Gordon RY, Halbert SC, French B, Morris PB, Rader DJ. Red yeast rice for dyslipidemia in statin-intolerant patients: a randomized trial. Ann Intern Med. 2009;150(12):830,9, W147-9.
2. Hong MY, Seeram NP, Zhang Y, Heber D. Chinese red yeast rice versus lovastatin effects on prostate cancer cells with and without androgen receptor overexpression. J Med Food. 2008;11(4):657-66.
3. Hong MY, Seeram NP, Zhang Y, Heber D. Anticancer effects of Chinese red yeast rice versus monacolin K alone on colon cancer cells. J Nutr Biochem. 2008;19(7):448-58.
4. Chen WP, Ho BY, Lee CL, Lee CH, Pan TM. Red mold rice prevents the development of obesity, dyslipidemia and hyperinsulinemia induced by high- fat diet. Int J Obes (Lond). 2008;32(11):1694-704.
5. Lu Z, Kou W, Du B, Wu Y, Zhao S, Brusco OA, et al. Effect of Xuezhikang, an extract from red yeast Chinese rice, on coronary events in a Chinese population with previous myocardial infarction. Am J Cardiol. 2008;101(12):1689-93.
Conflict of Interest:
None declared
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The Statin Dilemma In Aching Patients
Submit responseIt is with great interest that I read the article entitled "Red Yeast Rice for Dyslipidemia in Statin-Intolerant Patients: A Randomized Trial" by Becker et al. This preliminary study of 62 patients is a launching point for studying the role of red yeast rice as a complementary therapy in treating dyslipidemic patients in general. As a rheumatologist, I have consulted on many patients with myalgias due to statins and just recently have also found it useful in this patient population. Further, a heightened cardiovascular risk in RA has prompted the use of lipid lowering agents in "aching" patients. However, before red yeast rice is accepted there are several areas that need to be addressed. First, variability in preparations can lead to different results. Differences in manufacturing should be standardized. This has been a major concern with other products such as glucosamine and omega three preparations. Next, MRI and muscle histiological studies with biopsies and electrochemical studies could lead to further discoveries in muscle pathophysiology. Lastly, randomized controlled double blinded studies with appropriate power to ensure the positive benefit of red yeast rice are a must. In summary, I applaud this initial effort and hope the above studies are performed to make red yeast rice standard therapy in dyslipidemia.
Conflict of Interest:
None declared
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A statin is a statin is a statin
Submit responseRed yeast rice can cause side effects just like a statin. There have been reports of red yeast rice - associated myopathy (1) and hepatitis (2). This is because patients are actually treated with a statin (Red yeast rice contains lovastatin and other HMG-CoA reductase inhibitors) and in a much higher dose than they think (Red yeast rice inhibitors of HMG-CoA reductase inhibitors metabolism). Red yeast rice even depletes CoQ10 just like any other statin (3). In conclusion, this study demonstrates that "statin associated myopathy" does not occur if patients are unaware that they are treated with a statin....
References
1. Br J Clin Pharmacol. 2008;66:572-4; South Med J. 2003;96:1265-1267; Ann Intern Med. 2006;145:474-5
2. J Hepatol. 2009;50:1273-7; Ann Intern Med. 2008;149:516-7
3. J Am Geriatr Soc. 2006; 54:718-20; Br J Nutr. 2005; 93:131-5
Conflict of Interest:
None declared
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Red Yeast Rice for Statin Intolerant Cardiovascular Patients
Submit responseWhile alternative medications are controversial they are a realistic part of medical practice since many patients take them. The exact usage of alternative medications is unknown but one estimation is that at least 18% of all medications, including prescriptions, are alternative(1). When patients use these medications without the awareness of their physician, serious problems can develop due to side effects and interactions with prescription medications. However, when taken as part of physician- directed management, some alternative medications, such as red yeast rice (RYR), may have value for certain patients.
Becker et al performed a small single-site, single-practice study in Philadelphia to test the effectiveness of RYR, an alternative medication with naturally-occurring monacolin K (lovastatin), on patients with previous statin-associated myalgias (SAM). The study randomized 31 patients to RYR (from a single source) 1,800 mg twice daily and 31 patients to placebo(2). The RYR resulted in significant reductions in both total cholesterol and low density lipoprotein cholesterol levels over 24 weeks without evidence of myalgia or increased creatine phosphokinase. Although Becker et al noted that the lovastatin in RYR may be the significant cholesterol lowering agent, other constituents including other mevinic acids (monacolins) likely contributed to the study’s favorable outcome(3). Becker et al concluded that RYR can be effective for cholesterol reduction and calculated that the RYR used in their study yielded the equivalent of only 6 mg of lovastatin(2). These authors also quote an SAM occurrence of 10%, which seems consistent with current conventional statin therapy.
Although Becker et al have shown that RYR is apparently effective for the SAM patient, is it safe? Evaluation of RYR preparations has shown monacolin K (lovastatin) variation of 0.15 to 5 mg per 600 mg tablet(3). This variation may be a concern as, for the SAM patient, the administration of a statin of known potency administered just twice a week has been shown to improve patient tolerance(4). Another concern about widespread application of RYR for SAM patients is that of all the available statins, lovastatin has the highest incidence of fatal rhabdomyolysis(5). Therefore, practicing physicians and patients need to be aware of the variations in RYR potency, stick to a specific source to maximize dosing consistency and be aware of the risks and symptoms of excess potency and excessive doses.
Some patients are opposed to or afraid of taking prescription statin medications but will agree to take a natural alternative—in this case, RYR. Note, however, that cost should not be the reason due to the availability of such programs as the Walmart $4 prescriptions(6). For patients at high cardiovascular risk, RYR is certainly better than not taking any statin. In conclusion, while widespread use of any alternative medication in the absence of physician direction is not recommended, RYR may have value when used consistently and with physician-directed care.
REFERENCES
1. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. JAMA. 1998;280:1569-75.
2. Becker DJ, Gordon RY, Halbert SC, French B, Morris PB, Rader DJ. Red yeast rice for dyslipidemia in statin-intolerant patients: a randomized trial. Ann Intern Med. 2009;150:830-9, W147-9.
3. Heber D, Lembertas A, Lu QY, Bowerman S, Go VL. An analysis of nine proprietary Chinese red yeast rice dietary supplements: implications of variability in chemical profile and contents. J Altern Complement Med. 2001;7:133-9.
4. Gadarla M, Kearns AK, Thompson PD. Efficacy of rosuvastatin (5 mg and 10 mg) twice a week in patients intolerant to daily statins. Am J Cardiol. 2008;101:1747-8.
5. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med. 2002;346:539-40.
6. Walmart $4 Prescriptions Program. 2009.
Conflict of Interest:
None declared
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Think twice before suggesting red yeast rice to statin-intolerant patients
Submit responseWe read with interest the recent trial by Becker et al on the effects of red yeast rice in statin-intolerant patients (1). The results are certainly interesting, but the safety profile of read yeast rice when used in the “real world” should not be underestimated.
We recently conducted an analysis in the Italian ADR database of natural health products (including herbal drugs and food supplements), describing 4 cases of myopathies associated with red yeast rice use (dose range 200-1200 mg/die, no available data on monacolins content) (2). Each patient reported muscle pain and increased CPK ranging from 288 to 401 IU/l. The time-to-onset ranged between 2 and 6 months (6 months in a statin-intolerant subject). After product withdrawal, complete recovery was achieved in three cases, while a statin-intolerant patient developed a persistent increase in CPK for several months.
Although this cases of myopathy could not be considered conclusive in defining the safety profile of red yeast rice, the same can be said for the trial by Becker et al. In fact, due to their design, clinical trials are typically unsuited in the definition of drug safety, a feature that is usually let to post-marketing surveillance. Indeed the number of enrolled subjects is quite low (n=62), probably adequate to define the proposed efficacy outcomes, but certainly inadequate to obtain a significant information on safety.
The fact that all patients were statin-intolerant could increase the sensitivity of the study, with a myalgia recurrence rate (7%) lower than that expected in patients challenged with a second statin (57%). Although this could support the hypothesis that recurrence of myalgia is lower in statin-intolerant patients exposed to red yeast rice than in those exposed to a different statin (no direct comparison was anyway conducted in this sense with appropriate statistical analyses), we strongly believe that physicians should still be cautious, in order to avoid an overestimation of this product’s safety.
The fact that red yeast rice is widely available as a food supplement (though containing many pharmacologically active molecules, such as monacolin K and congeners) could in fact lead statin-intolerant patients to assume this product without any medical advice, exposing them to a significant risk of myopathy. This is exactly what happened in the four Italian patients reported by us (2), who underestimated the risk of myalgias, myopathy and rhabdomyolisis due to red yeast rice, considered by them a “natural” lipid lowering product, a food supplement, and, therefore, absolutely safe.
References
1. Becker DJ, Gordon RY, Halbert SC et al., Red Yeast Rice for Dyslipidemia in Statin-Intolerant Patients. A Randomized Trial., Ann Intern Med. 2009;150:830-839.
2. Lapi F, Gallo E, Bernasconi S et al. Myopathies associated with red yeast rice and liquorice: spontaneous reports from the Italian Surveillance System of Natural Health Products., Br J Clin Pharmacol. 2008;66:572-574
Conflict of Interest:
None declared
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Red Rice Yeast for Dyslipidemia in Statin-Intolerant Patients
Submit responseBecker et al (1) conclude that red yeast rice might be a treatment option in subjects who cannot tolerate statins. The trial studied subjects who had previously discontinued statins secondary to myalgias but excluded those with the more serious diagnoses of myositis or rhabdomyolysis.
The authors indicate that the daily dose of red yeast rice is equivalent to only 6 mg of lovastatin and is much lower (and presumably safer) than the recommended daily dose of lovastatin tablets which is 20- 40 mg. The active component of lovastatin is its metabolite, lovastatin hydroxyacid. The only pharmacokinetic study of red yeast rice compared it to 20 mg lovastatin tablets (2). This study was unfortunately confounded by the co-administration of grapefruit juice. However, the Cmax (4.31 vs 4.55 ng/ml) and area under the curve (29.47 vs 31.63 ng.hr/ml) for lovastatin hydroxyacid following red yeast rice were similar to another study where 80 mg lovastatin was administered without grapefruit juice (3). Furthermore, there are many other substances in red yeast rice apart from lovastatin including sapogenins, citrinin and various colored polyketide pigments, which are potential inhibitors of CYP3A4 and/or P glycoprotein. Therefore, the oral dose of lovastatin in red yeast rice might not reflect the subsequent blood concentrations of lovastatin or its active metabolite following administration of red yeast rice. Until appropriate pharmacokinetic studies of red yeast rice are performed (that is, without confounding co-administration of grape fruit juice), this issue is unresolved.
Red yeast rice is a sweet smelling substance therefore it is possible that the subjects were unblinded unless the placebo was similar in smell. This is important since the key outcome of myalgia pain is subjective. Of note, the increase in CPK was slightly greater in the treatment group than the placebo group and the change almost reached statistical significance at 12 weeks (P=0.057). Given only 30 subjects were in the treatment group, the statistical power to differentiate any effect was small. Muscle injury with red yeast rice is a concern because there are several recent reports of myopathy with red yeast rice (eg (4), including a series of four cases (5).
Given these issues, considerable caution is necessary before recommending red yeast rice to subjects who cannot tolerate statins. However, the conclusions regards the concomitant lifestyle program are very welcome and highly applicable.
References
(1) Becker DJ, Gordon RY, Halbert SC, French B, Morris PB, Rader DJ. Red yeast rice for dyslipidemia in statin-intolerant patients. Ann Intern Med. 2009;150:830-839.
(2) Li Z, Seeram NP, Lee R, Thames G, Minutti C, Wang HJ, Heber D. Plasma clearance of lovastatin versus chinese red yeast rice in healthy volunteers. J Altern Complement Med. 2005;11:1031-1038. [PMID: 16398595]
(3) Mignini F, Tomassoni D, Streccioni V, Traini E, Amenta F. Pharmacokinetics and bioequivalence study of two tablet formulations of lovastatin in healthy volunteers. Clin Exp Hypertens. 2008;30:95-108. [PMID: 18293165]
(4) Mueller PS. Symptomatic myopathy due to red yeast rice. Ann Intern Med. 2006;145:474-475. [PMID: 16983142]
(5) Lapi F, Gallo E, Bernasconi S, Vietri M, Menniti-Ippolito F, Raschetti R, Gori L, Firenzuoli F, Mugelli A, Vannacci A. Myopathies associated with red yeast rice and liquorice: spontaneous reports from the Italian Surveillance System of Natural Health Products. Br J Clin Pharmacol 2008;66:572-574. [PMID: 18637891]
Conflict of Interest:
None declared