It is well recognised that in most subjects, liver cholesterol synthesis is the primary determinant of LDL-C plasma levels. Since 2011, the European Cardiology Society and European Atherosclerosis Society recommendations have suggested the use of red yeast rice (RYR) extract, an inhibitor of endogenous cholesterol synthesis, in the treatment of mild hypercholesterolemia. This advice was recently reiterated by the International Lipid Expert Group.

Hypercholesterolemia is a well-known dosage- and time-dependent cardiovascular disease (CVD) risk factor, with the risk being inversely proportional to the plasma level of low-density lipoprotein cholesterol (LDL-C) and directly related to the amount of the time the person is exposed to elevated LDL-C.

Naturally occurring substances and their potential in the treatment of hypercholesterolemia

Given the comparatively large prevalence of individuals with suboptimal LDL-C levels in the general population (approximately 50%) and the limited effect of lifestyle changes on LDL-C levels (from 5 per cent to 10 per cent), single dietary components or natural compounds capable of further improving lipid pattern in the form of proper dietary and physical activity practises have recently received a lot of interest.

The third report of the National Cholesterol Educational Program made the first systematic recommendation for the use of dietary supplements and nutraceuticals to optimise plasma lipid levels. Plant sterols, soy proteins, soluble fibres, and polyunsaturated fatty acids were advised as supplements to a balanced diet in these recommendations. Polyunsaturated fatty acids, on the other hand, have a triglyceride (TG)-lowering effect, while soy proteins' lipid-lowering effectiveness tends to be less significant than previously assumed. Plant sterols and stanols, as well as soluble fibres, have been shown to help lower cholesterol levels by inhibiting dietary and biliary cholesterol absorption at the bowel level.

Bioactive substances, pharmacodynamic and pharmacokinetic features of red yeast rice

RYR is a nutraceutical made from rice (Oryza sativa) fermented with yeast (in general Monascus purpureus). Pigments that are by-products of the fermentative metabolism process are responsible for the characteristic red colouration.

Sugars (25–73%), mostly starch, proteins (14–31%), water (2%–7%), fatty acids (1%–5%), pigments, sterols, and isoflavones are all contained in RYR. During the fermentation process, the yeast enriches the rice with monacolins, which are polyketides that have clinically observable cholesterol-lowering properties. Monacolin concentrations of RYR dietary supplements usually range from 1.9 per cent to 1.9 per cent.

The tendency of monacolins to reversibly suppress the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a central enzyme in the cholesterol synthesis process which is also blocked in a greater way by statins, is the major mechanism of action of RYR in reducing cholesterol.

Evidence of RYR's lipid-lowering activity in clinical trials

Some meta-analyses of randomised clinical trials (RCTs) have established RYR's lipid-lowering effectiveness, the most recent of which involved 20 trials and 6,663 participants and finding that, after 2 to 24 months of treatment, RYR lowered LDL-C on an average by 1.02 mmol/l (95 per cent confidence interval: 1.20 to 0.83) (39.4 mg/dl) compared to placebo, which was comparable to the reduction achieved with low-intensity/low-dose statins (pravastatin 40 mg, simvastatin 10 mg, lovastatin 20 mg).

The combination of RYR (3 mg monacolin K) and berberine is the most researched lipid-lowering nutraceutical combination (500 mg). A meta-analysis of 14 RCTs involving 3,159 participants found that the RYR-berberine combination would reduce plasma LDL-C by 0.61 mmol/l (23.6 mg/dl, leading to a 14.7 percent reduction) (p 0.001), HDL-C by 0.07 mmol/l (2.7 mg/dl) (p 0.001), TG by 0.16 mmol/l (14.2 mg/dl) (p 0.001), and glucose by −0.14 mmol/l (−2.52 mg/dl) (p = 0.010).

Evidence of RYR's effect on cardiovascular risk biomarkers and hard outcomes in clinical trials

• Since RYR inhibits LDL-C synthesis in a statin-like way, we should anticipate RYR supplements to improve laboratory and instrumental biomarkers of cardiovascular disease.
• Following a high-fat meal, lipid parameters, levels of high-sensitivity C-reactive protein (hsCRP), and flow-mediated dilation (FMD) were measured in a study involving 50 patients with coronary artery disease who were administered with 1,200 mg/day of RYR or placebo for six weeks (800 calories, with 50 g of fat, 28 g of protein, and 60 g of carbohydrates, at 0 and 4 hours).
• At the 6-week follow-up, the RYR group had a substantial decrease in total cholesterol, LDL-C, TG, and hsCRP serum levels, as well as an enhancement in postprandial and preprandial FMD (p 0.001), while the placebo group had no significant improvements in serum lipids or FMD. Other clinical trials have shown that RYR has a similar effect on endothelial activity.
• Additionally, RYR has been shown to reduce arterial stiffness in patients with moderate hypercholesterolemia as well as patients with antiretroviral-related dyslipidemia.
• Treatment with RYR has reduced the risk of cardiovascular and overall mortality by 30% and 33%, respectively, as well as the need for coronary revascularization by one-third.

Safety of RYR in the normal population and in statin-intolerant individuals

RYR supplements are generally safe and well-tolerated. However, the United States Food and Drug Administration does not control RYR supplements, and there has been a significant variation in the amount of monacolin K in available RYR preparations. Furthermore, questions about the safety of RYRs have recently been raised following the release of a few case reports alleging toxicity.

The quality of the medication assumed, the frailty of the patient assuming the product, and the likelihood of pharmacological interactions all play a role in RYR safety. Regardless of the fact that monacolin K has the same metabolism and mechanism of action as lovastatin, RYR appears to be well accepted by previously statin-intolerant subjects, particularly when regular doses of monacolin K between 3 mg and 10 mg are used. Adding RYR to the baseline therapy of ezetimibe raised the number of statin-intolerant participants who reached the target LDL-C objective thus lowering the risk of adverse events.

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[1] Arrigo F.G. Cicero, Federica Fogacci, Alberto Zambon, Red Yeast Rice for Hypercholesterolemia: JACC Focus Seminar, Journal of the American College of Cardiology, Volume 77, Issue 5, 2021, Pages 620-628, ISSN 0735-1097, https://doi.org/10.1016/j.jacc.2020.11.056.

[2] 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Atherosclerosis, 290 (2019), pp. 140-205

[3] Lipid-lowering nutraceuticals in clinical practise: position paper from an International Lipid Expert Panel. Nutr Rev, 75 (2017), pp. 731-767

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.