Red Yeast Rice: Nature’s Statin?

June 30, 2011


By Joshua Farhadian

Faculty Peer Reviewed

M. K.  is a 61-year-old female with hypercholesterolemia who presents to clinic complaining of muscle pain and weakness.  She reports that one month after beginning statin therapy she developed myalgias and immediately stopped taking her medication.  She states that she wants to control her cholesterol level, since both of her parents died of heart disease; however, she is hesitant to take a prescription medication due to the side effects she experienced.  She asks you about red yeast rice (RYR). She says that her neighbor noticed a dramatic drop in her LDL after starting this dietary supplement.

 Red yeast rice (Monascus purpureus) is a food additive used in Chinese cooking that has been found to decrease serum cholesterol levels.[1] Its popularity has been rapidly growing in the United States. American spending on RYR increased nearly 80% from 2005 to 2008, with sales of $20 million in 2008.[2] To synthesize RYR, red yeast is cultured on white rice and then fermented. The yeast is subsequently inactivated and the rice-yeast product is converted to a powder.  Chemical analysis reveals that RYR contains 10 different types of monacolins, which are known as 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors. A particularly interesting component of RYR is monacolin K, which is chemically identical to lovastatin and has been shown to significantly reduce cholesterol and triglyceride levels. Other components of RYR that are likely to lower cholesterol levels are sterols (including beta-sitosterol, campesterol, stigmasterol, and sapogenin), isoflavones, and monounsaturated fatty acids.

 Animal studies have provided evidence in support of the lipid-lowering effects of RYR. In rabbits, Xuezhikang, a type of RYR extract, lowered total cholesterol by 44% and 59% at doses of 0.4 mg/kg and 0.8 mg/kg, respectively.[3] The same study found that RYR also prevented increases in serum total cholesterol (P < 0.05) and triglyceride concentrations (P < 0.01) among quail exposed to an atherogenic diet.

 The statin-like effect of RYR has been upheld in many human studies as well. In a 1999 randomized, double-blind, placebo-controlled 12-week trial of RYR 2.4 g per day in an American population with hypercholesterolemia, RYR was found to decrease total cholesterol  16%, LDL-cholesterol 23%, and triglycerides 7%.[4]  In a similar 2005 8-week trial of RYR 600 mg twice a day in a Chinese population with hypercholesterolemia, RYR was even more efficacious, lowering total cholesterol 21.5%, LDL-cholesterol 27.7%, and triglycerides 15.8%.[5] The difference in RYR’s effect on cholesterol in the two trials can be attributed to the attenuation of RYR’s pharmacological effect with prolonged use, the different ethnicities of the study population, and differences in the baseline total and LDL-cholesterol levels (249.8 and 172.6 mg/dl in the Heber study, 281.1 and 200.8 mg/dl in the Lin study). 

 Animal studies have indicated that RYR has a high therapeutic index. Mice challenged with a single dose of RYR extract 533 times the typical human dose demonstrated no toxicity.[6] Similarly, rats treated with doses of 5.0 g/kg/d for 90 days had no evidence of toxicity based on histopathology or liver transaminase levels.[7]

 The incidence of myalgias caused by RYR was tested by Becker and colleagues in a 24-week, randomized, double-blind, controlled trial of 62 patients with dyslipidemia and a history of discontinuation of statin therapy due to myalgia.[8] Ninety-three percent of subjects with a history of statin-associated myalgia were able to tolerate 1.8 grams of RYR daily for 24 weeks without a recurrence of myalgia. Furthermore, RYR did not increase the mean brief pain inventory (BPI) score, which represents reported average pain over the past month on a scale of 1-10.  The mean BPI score of the RYR group was 1.4 at baseline and 1.2 at week 24. There was also no significant difference in creatine phosphokinase, aspartate aminotrasferase, or alanine aminotransferase levels between treatment and control groups. The study’s authors suggest that other compounds in RYR besides monacolin K may also inhibit HMG-CoA reductase. These same compounds may also be less likely to deplete mevalonate metabolites distal to HMG-CoA reductase that are believed to mediate statin-induced muscle injury, such as guanosine triphosphate-binding regulatory proteins and intracellular isoprenoids, including ubiquinone. 

 The Becker study has two notable shortcomings.  First, the median time of myalgia onset with statin therapy has been reported to be between 1 and 6.3 months, but can occur at any time, with a range of onset from 1 week to 48 months.[9,10] This study was only 24 months long and may have missed late-onset myalgia. Second, the dose of RYR given to the treatment group was equivalent to a daily lovastatin dose of only 6 mg, which is far less than the established therapeutic dose of 20 to 40 mg/day. It is possible that at higher doses RYR can also lead to myalgias.

 In 2010, Halbert and colleagues published the results of a double-blind, randomized, controlled head-to-head trial comparing RYR with pravastatin.[11] A total of 43 American adults with dyslipidemia and a history of statin discontinuation due to myalgia were randomly assigned to RYR 2.4 g twice daily or pravastatin 20 mg twice daily for 12 weeks. After 12 weeks, no significant differences were found between the RYR group and the pravastatin group in the percentage change of total cholesterol, LDL-cholesterol, or triglycerides from baseline to week 12.  The RYR group had mean decreases in total cholesterol (23%), LDL-cholesterol (30.2%), and triglycerides (7.8%). The pravastatin group had mean decreases of 19.6%, 27%, and 7%.  In addition, this study found no difference between the two groups in the frequency of reported myalgias.

 While the Becker study indicated that individuals with statin associated myalgia can tolerate RYR, the Halbert study demonstrated that pravastatin is tolerated equally well. Both studies are plagued by small sample size and short duration.  A longer, large-scale trial comparing the efficacy and side effects of RYR and pravastatin is needed. 

 At the present time, RYR is not a suitable substitute for statin therapy.  Although the chemical composition of RYR was known in all of these studies, there is a lack of consistency among different manufacturers.  In a study of 9 proprietary RYR supplements, total monacolin content varied from 0% to 0.58% and only 1 of 9 preparations had the full complement of 10 monacolin compounds.[12] Furthermore, a measurable level of citrinin, which is a nephrotoxic byproduct of RYR fermentation, was found in 7 of the 9 preparations.

 The Food and Drug Administration currently bans the sale of any RYR with appreciable levels of monacolins due to the presence of unregulated levels of lovastatin. Given recent preliminary evidence suggesting that RYR is as effective at lowering total cholesterol, LDL-cholesterol, and triglycerides as pravastatin, this supplement will likely be researched more carefully in the near future. Based on the results of such studies, RYR extract may eventually become available as an alternative method for lowering serum cholesterol levels in patients with hypercholesterolemia.

 Commentary by Dr. Arnold Schwartzbard

There are other options for statin-intolerant patients that need to be considered. Published options include changing to another statin, using other non-statin agents, or using a statin on a less than daily basis. When symptoms develop with statin therapy, we prefer to use another statin or try less than daily dosing before using red yeast rice extract. The rationale has to do with established outcome benefits for statin therapy that do not exist for red yeast rice extract.

Joshua Farhadian is a 4th year medical student at NYU School of Medicine

Peer reviewed by Arthur Schwartzbard , MD Assistant Professor, Department of Medicine, Division of Cardiology, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References

1.  Talbott SM, Hughes K. The health professional’s guide to dietary supplements. Baltimore; Philadelphia: Lippincott Williams & Wilkins;2007:444.

2.  Supplement Business Report 2009. Boulder, CO: Nutrition Business Journal; 2009:44.  http://sjhg.org/journalclub/march2010/JC%20March%20TK.pdf

3.  Zhu Y, Li CL, Wang YY. Effects of Xuezhikang on blood lipids and lipoprotein concentrations of rabbits and quails with hyperlipidemia. Chin J Pharmacol. 1995;30:4–8.

4.  Heber D, Yip I, Ashley JM, Elashoff DA, Elashoff RM, Go VL.  Cholesterol-lowering effects of a proprietary Chinese red-yeast-rice dietary supplement.  Am J Clin Nut. 1999;69(2):231-236.  http://www.ncbi.nlm.nih.gov/pubmed/9989685

5.  Lin CC, Li TC, Lai MM. Efficacy and safety of Monascus purpureus Went rice in subjects with hyperlipidemia. Eur J Endocrinol. 2005;153(5):679-686.

6.  Li CL, Li YF, Hou ZL. Xuezhikang toxicity study. Bull Chinese Pharmacol Soc. 1995;12:3.

7.  Wang J, Su M, Lu Z, 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.

8.  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.  http://www.ncbi.nlm.nih.gov/pubmed/19528562

9.  Bruckert E, Hayem G, Dejager S, Yau C, Bégaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients–the PRIMO study. Cardiovasc Drugs Ther. 2005;19(6):403-414.

10  Hansen KE, Hildebrand JP, Ferguson EE, Stein JH. Outcomes in 45 patients with statin-associated myopathy. Arch Intern Med. 2005;165(22):2671-2676.

11.  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(2):198-204.

12.  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(2):133-139.  http://www.ncbi.nlm.nih.gov/pubmed/11327519