School of Medicine, University of Zagreb

Association of Teachers in General Practice/ Family Medicine (ATGP/FM)

Croatian Academy of Medical Sciences (CAMS)

You must have experienced that a patient refused recommended therapy, especially therapy of statins, in order to reduce lipids in their blood by healthy life-style and healthy eating habits. When they asked you what you thought about the use of red rice, were you motivated to learn more about it?

Its use has been documented as far back as the Tang Dynasty in China in 800 AD in the Chinese pharmacopoeia. It was being recommended against digestive, intestinal, as well as blood circulation problems. 

Red rice powder (Zhi Tai), and alcohol extract (Xue Zhi Kang) were used. Red rice is traditionally used today in Chinese cuisine as food seasoning, supplement to drinks or cosmetic products, and as a natural food preservative, spice and as a raw material for rice wine.

Today, red rice is classified as food supplement produced by the fermentation of “ordinary” rice Oryza stativa by the help of yeast Monascus purpureus. The product of that fermentation are monacolins which inhibit the synthesis of cholesterol in the liver. One type of monacolin, monacolin-K, (the inhibitor of HMG-CoA reductase) is known in the pharmaceutical industry as mevinolin or lovastatin, only the doses are lower in food supplements (3 − 5 mg in the pill, with the recommended dosage of 10 mg) as compared with lovastatin prescribed as medicine (10, 20 and 40 mg in one pill). Red rice has a similar therapeutic effect due to containing lovastatin, however it is very important to be aware that side effects and interactions with other drugs are the same as if one is taking the drug lovastatin.

Brief overview of statins. Inhibitors of hydroxy-3-methyl-glutaryl CoA (HMG-CoA) reductase, colloquially statins, are among the most frequently prescribed drugs in the world. They reduce the concentration of cholesterol in the blood, thus reducing the risk of myocardial infarction, ischemic cerebral infarction and the development of peripheral artery disease. Furthermore, experimental and clinical research showed that statins improve the function of the endothelium and/or stabilise atherosclerotic plaque, show an anti-inflamatory, imunomodular and neuroprotective effect (reducing the risk of dementia), also positively affecting the bone metabolism and delaying the development of chronic kidney diseases. 

These pleiotropic effects can be explained by the fact that statins, besides the cholesterol synthesis, also inhibit the synthesis of many other metabolites. Side effects, like rhabdomyolysis, are rare. However, muscle pain is very common, which causes a termination of treatment, often by patients themselves.

Studies. The efficacy of red rice has been confirmed in more than 30 clinical studies available in Pubmed database. Almost all studies showed a reduction of the levels of total and LDL cholesterol in individuals taking red rice with the active ingredient as compared to those taking placebo. Meta analysis of seven studies on 10,699 patients with myocardial infarction and borderline values of lipid profile, via The Cochrane Collaboration framework guidelines proved the efficacy of red rice concentrate (1200mg/day) on the cardiovascular outcome and lipid profile.

However, it is the addition of monacolin-K (lovastatin) in the fermentation of red rice which causes health workers’ concerns about the health of their patients due to the contraindications of statins and their interactions with other drugs. Thus Food and Drug Administration (FDA) warned consumers to avoid food supplements like red rice which are sold online, because of possible myopathy or kidney damage.

Croatian Agency for Medicinal Products and Medical Devices warned health workers in 2012 that in case of unsupervised consumption of such food supplements, there was certain risk of side effects and interactions characteristic for statins, especially in patients who have previously experienced side effects of statins (e.g. muscle and liver damage). Since its efficacy is clearly proved, it can help in the treatment of hypercholesterolemia, but the decision about its administration should not be made without consultations with the physician, who will take into account contraindications, precaution measures and possible interactions common for statins.

 

Unresolved issues regarding the classification of red rice as drug or food supplement

  • Is the consumption of red rice as a food supplement safe? Although red rice is classified as a food supplement, some Monascus purpureus yeast strains produce a dangerous compound citrinin, which may cause the kidney and the liver damage. Therefore, many pharmaceutical companies, when they produce food supplements based on red rice, conduct additional analyses of the presence of citrinin in the raw material.
  • Uncertain efficacy of food supplements regarding the varying quality and quantity of the ingredients and differences in the legislation of research into drugs and food supplements. There is the question if the red rice extract used in studies and that available on the free market are identical. The composition and the amount of the active substance in the preparations from different producers may vary. Thus Heber et al. showed that in nine examined preparations the values of monacolin were different, while citrinin was found in seven of them.
  • Special caution is recommended when purchasing the preparation. Furthermore, it is important to follow the recommended dosage, which is 1200mg/day for concentrated red rice, usually during 3-6 months. After that, it is necessary to test the effectiveness of the preparation for every individual. 
  • Why should red rice be emphasized as a natural ingredient, food supplement or “natural” medicine, when effective substance is chemically identical to drug lovastatin (inhibitor HMG- CoA reductase) which is used in the treatment of hypercholesterolemia, only in lower doses. Special caution is due to possible interaction, because it is not classified as drug. 
    • Drug interactions. Being a food supplement, red rice is classified as food. Therefore studies related to drug interactions are vague. However, since monacolin-K is in fact lovastatin, common interactions with lovastatin are applicable. Recommendations include avoiding alcohol and drugs which interfere with liver functioning, inhibitor of cytochrome P450, anticoagulants, anti-inflammatory drugs and some drugs for hypertension and thyroid gland diseases. Patients need to be aware that red rice contains lovastatin and a decision to eat this healthy food may be dangerous for patients taking statins.
    • Interactions with food. It is not recommended to consume grapefruit juice, coenzyme Q10, astaxanthin, zinc and herbal food supplements produced from ginkgo, garlic and sabal palmetto.

 

However, in 2019, the European Society of Cardiology (ESC) / European Atherosclerotic Society (EAS) develop “Guidelines for the management of dyslipidemias”, with the main message “the lower, the better”, regarding the values of LDL cholesterol in the primary, and especially secondary prevention of cardiovascular diseases. There is very little about red rice, due to its low efficacy and, consequently, the inappropriateness of treating hypercholesterolemia with red rice. Only in one randomized study from China, partially purified extract of RYR reduced relapse in patients with coronary disease by 45%

The fact is that food supplements, compared to drugs, are not subjected to strict mechanisms of control. Consequently, the quality and quantity of ingredients cannot be guaranteed. There are peer review reports about papers proving that such food supplements are not recommendable for patients with hypercholesterolemia, primarily due to a lack of uniformity of their production. Such an approach to a food supplement containing drug, does not guarantee the purity of ingredients nor the safety and quality of the product and, accordingly, it cannot guarantee the outcome of its consumption. The variability of the amount of lovastatin in various red rice preparations is very high and it is difficult to predict and understand the relationship between the dosage and the efficacy of such preparations. The effect of regulating the level of cholesterol in the serum considerably varies among red rice preparations, depending on the dosage of lovastatin in them.

 

Conclusion

Today, at the time of personalized medicine, the family physician needs to be aware of the inconsistent composition of red rice and thus the varying success in attaining the goal in treating hypercholesterolemia. Red rice has been included in the ESC / EAS Guidelines as a food supplement for life-style changes, because of the proven efficacy of monacolin-K, i.e. lovastatin which is used as a drug but in higher doses. However, the attitude in the Guidelines postulating “the lower, the better” is that red rice has limited practical value, primarily for adults (not younger than 18) who have borderline values of LDL cholesterol (≤ 3.0 mmol/L), or total cardiovascular risk < 1% according to the SCORE charts, where treatment with statins, and especially other drugs for hypercholesterolemia are not recommended. Certainly, under the premise that the active component in red rice, monacolin K (lovastatin) were purified, controlled and stable.

Literature:

  1. Huang CF, Li TC, Lin CC, et al. Efficacy of Monascus purpureus Went rice on lowering lipid ratios in hypercholesterolemic patients. Eur J Cardiovasc Prev Rehabil 2007 Jun;14(3):438-40.
  2.  Liu BH, Wu TS, Su MC, et al. Evaluation of citrinin occurrence and cytotoxicity in Monascus fermentation products. J Agric Food Chem 2005;53(1):170-175. 
  3. Sirtori CR. The pharmacology of statins. Pharmacol Res. 2014; 88:3-11. 
  4. Heber S, Audra L, Qing-Yi L, et al. An analysis of nine propriety Chinese red yeast rice dietary supplements: Implications of variability in chemical profile and contents. J Altern Complement Med. 2001;7(2):133–139. 
  5. Yinhua LiLong JiangZhangrong JiaWei XinShiwei YangQiu Yang, * and Luya Wang. A Meta-Analysis of Red Yeast Rice: An Effective and Relatively Safe Alternative Approach for Dyslipidemia. PLoS One. 2014; 9(6): e98611.
  6. Klimek M, Pharm D,  Shang Wang,  Adeleye Ogunkanmi. Safety and Efficacy of Red Yeast Rice (Monascus purpureus) as an Alternative Therapy for Hyperlipidemia. P T. 2009; 34(6): 313–327. 
  7. Bunleu SungthongChenchira YoothaekoolSornsalak Promphamorn, and Wiraphol Phimarn. Efficacy of red yeast rice extract on myocardial infarction patients with borderline hypercholesterolemia: A meta-analysis of randomized controlled trials. Sci Rep. 2020; 10: 2769.
  8. Halmed. Croatian Agency for Medicinal Products and Medical Devices. Overview of the risks of food supplements containing red rice for patients who have experienced side effects of statins http://www.almp.hr/?ln=hr&w=novosti&d=2012&id=617&p=1. Accessed on 20 May 2020.
  9. ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk https://www.escardio.org/static_file/Escardio/Guidelines/publications/DYSLIPguidelines-dyslipidemias-FT.pdf. Assessed 25 May 2020. 

Biserka Bergman Marković