Red Yeast Rice for the Improvement of Lipid Profiles in Mild-to-Moderate Hypercholesterolemia: A Narrative Review

Reducing low-density lipoprotein cholesterol (LDL-C) levels is a key target for lowering cardiovascular risk and preventing atherosclerotic cardiovascular disease (ASCVD). Red yeast rice (RYR) is a nutraceutical widely used as a lipid-lowering dietary supplement. The main cholesterol-lowering components of RYR are monacolins, particularly monacolin K, which is structurally identical to lovastatin and targets the same key enzyme of cholesterol biosynthesis. RYR supplementation reduces LDL-C levels by approximately 15–34% versus placebo, with a similar effect to low-dose, first-generation statins in subjects with mild-to-moderate dyslipidemia. RYR has also demonstrated beneficial reductions of up to 45% versus placebo in the risk of ASCVD events in secondary prevention studies. RYR at a dose that provides about 3 mg/d of monacolin K is well tolerated, with an adverse event profile similar to that of low-dose statins. RYR is therefore a treatment option for lowering LDL-C levels and ASCVD risk for people with mild-to-moderate hypercholesterolemia who are ineligible for statin therapy, particularly those who are unable to implement lifestyle modifications, and also for people who are eligible for statin therapy but who are unwilling to take a pharmacologic therapy.


Introduction
Hypercholesterolemia, especially elevated low-density lipoprotein cholesterol (LDL-C), is a major modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD) [1,2]. Guidelines recommend lifestyle changes and, when indicated, pharmacologic interventions, to lower LDL-C levels and decrease ASCVD risk [2][3][4]. However, some individuals with mild-to-moderate dyslipidemia and a low ASCVD risk who are not eligible for pharmacologic treatment may not achieve target LDL-C levels through lifestyle changes alone. These individuals, and also people who do not wish to take a pharmaceutical drug, might benefit from a nutraceutical such as RYR that helps them achieve lower LDL-C levels and lower their ASCVD risk.
The goal of treatment for hypercholesterolemia is to lower the burden of ASCVD and prevent ASCVD events such as myocardial infarction (MI), ischemic stroke, need for revascularization, and death [2]. Where pharmacologic intervention is recommended, statins form the mainstay of treatment [2][3][4]. Other lipid-lowering drugs such as ezetimibe, bempedoic acid, proprotein convertase subtilisin/kexin type 9 inhibitors, and inclisiran may be inaccessible to many people for a variety of reasons, such as high costs, lack of

Purpose and Outcome of Treatment
The management of LDL-C forms part of a comprehensive ASCVD risk-reduction strategy, which is based on individual CVD risk profiles and preferences [2,3]. Given that guideline recommendations for the management of dyslipidemia are based on ASCVD risk calculators, which are strongly dominated by age [2][3][4], many individuals do not reach the designated level of risk for intervention until middle age or older, leading to a delay in the initiation of therapy. However, by this time, such individuals may have been exposed to LDL-C levels for decades.
Prolonged reduction in LDL-C levels is associated with a substantially decreased risk of ASCVD [1]. A meta-analysis of data from 170,000 participants in 26 clinical trials of lipidlowering drugs demonstrated a reduction of approximately one-fifth in the risk of major ASCVD events per 1 mmol/L decrease in LDL-C in the secondary prevention setting, with a similar benefit in primary prevention [24]. Further meta-analyses have confirmed that the greater the absolute LDL-C reduction, the greater the ASCVD risk reduction [3]. Mendelian randomization studies indicate that, alongside absolute LDL-C level, the duration of exposure to higher LDL-C is significantly associated with ASCVD risk, demonstrating a cumulative impact of LDL-C throughout an individual's lifetime [25,26]. One such study examined data from >300,000 participants and showed that the prolonged exposure to lower LDL-C mediated by nine polymorphisms in six different genes (i.e., beginning from early life) was associated with a three-fold greater risk reduction per unit lower LDL-C versus intervention with a statin started later in life [25]. Overall, this indicates a rationale for early and prolonged lipid-lowering interventions to achieve lifetime risk reduction.
The recommended LDL-C goals in the ESC/EAS guidelines for the management of dyslipidemia are based on the patient's ASCVD risk, with goals of <116 mg/dL (<3.0 mmol/L) and <100 mg/dL (<2.6 mmol/L) for patients at low and moderate risk, respectively [3]. Tighter control of LDL-C is recommended for patients at high and very high risk, with targets of a ≥50% reduction in LDL-C from baseline and an absolute LDL-C <70 mg/dL (<1.8 mol/L) for high risk and <55 mg/dL (<1.4 mmol/L), or even <40 mg/dL (<1.0 mmol/L), in selected patients for very high risk [3].
Dietary modifications-avoiding trans fats, lowering intake of saturated fats and cholesterol, and increasing fiber intake-all lower LDL-C by levels 5-10% [3]. Additional lowering of LDL-C by nutraceuticals such as RYR might help people meet their LDL-C goals, particularly individuals with elevated LDL-C levels who do not qualify for treatment with statins because they have a low global CV risk [3] and those who are unwilling to use statins [27]. Other lipid-lowering nutraceuticals are beyond the scope of this review, but a selection of the preparations available is shown in Table 2. Table 2. Other nutraceuticals with lipid-lowering properties [6,14].

Mechanisms of Action Main Lipid-Lowering Component(s) Effects on Lipids Safety and Tolerability
Artichoke leaf extract

Metabolism of the Bioactive Components and Mechanism of Action of RYR
The main cholesterol-lowering effects of RYR are provided by monacolins, its main bioactive components. Monacolin K, the most abundant monacolin in RYR [28], occurs in two forms: the lactone (inactive) and hydroxyl acid (active) [28][29][30]. The proportion of the acid form has been reported to vary from 5% to 100%, depending on pH: at low pH, the lactone form predominates, whereas at neutral and acidic pH, the acid form predominates [5,28,29]. The lactone form of monacolin K is structurally identical to lovastatin [28,29]; therefore, similar to other statins, monacolin K is a reversible inhibitor of β-hydroxyβ-methylglutaryl coenzyme A reductase (HMG-CoAR), the enzyme catalyzing the rate-limiting step of cholesterol biosynthesis (Figure 1) [5]. Lovastatin is a prodrug that must be hydrolyzed to the acid form [5,28,29] because only this form bonds to key amino acid residues in the binding pocket of HMG-CoAR (differing from those bound by the lactone form), stabilizing the interaction between the two molecules [31]. By contrast, the acid form is naturally present in RYR, and this can result in differences in bioavailability and clinical profiles between RYR and lovastatin. In addition to inhibition of HMG-CoAR, statins have demonstrated actions at the transcription level, with increases in nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα), mediated by the Rhosignaling pathway, potentially explaining increases in high-density lipoprotein cholesterol (HDL-C) levels with statin therapy [32]. Statins also influence the expression of a wide range of other genes, including transcription factors involved in inflammation, proliferation, and differentiation [33,34], and cholesterol transporters in a range of tissues, including the liver, intestine, adipose tissue, and skin, and apolipoprotein A1 (apo-A1) in the liver ( Figure 2) [35]. This leads to an increased transfer of cholesterol to apo-A1, leading to a greater production of HDL. two forms: the lactone (inactive) and hydroxyl acid (active) [28][29][30]. T acid form has been reported to vary from 5% to 100%, depending on lactone form predominates, whereas at neutral and acidic pH, the acid [5,28,29]. The lactone form of monacolin K is structurally identical therefore, similar to other statins, monacolin K is a reversible inhib methylglutaryl coenzyme A reductase (HMG-CoAR), the enzyme limiting step of cholesterol biosynthesis ( Figure 1) [5]. Lovastatin is be hydrolyzed to the acid form [5,28,29] because only this form bond residues in the binding pocket of HMG-CoAR (differing from those b form), stabilizing the interaction between the two molecules [31]. B form is naturally present in RYR, and this can result in differences in clinical profiles between RYR and lovastatin. In addition to inhibit statins have demonstrated actions at the transcription level, with receptor peroxisome proliferator-activated receptor alpha (PPARα), m signaling pathway, potentially explaining increases in highcholesterol (HDL-C) levels with statin therapy [32]. Statins also influ of a wide range of other genes, including transcription factors involv proliferation, and differentiation [33,34], and cholesterol transporters including the liver, intestine, adipose tissue, and skin, and apolipopr the liver ( Figure 2) [35]. This leads to an increased transfer of ch leading to a greater production of HDL.  Similarly to lovastatin, CYP3A4 is involved in the metabolism of monacolins which are substrates of P-glycoprotein. Their bioavailability and safety could therefore be affected by interactions with other medicinal products and foods, although these potential effects are yet to be fully characterized [29,36]. Plasma concentrations of the hydroxy acid and lactone forms of monacolin K after ingestion of 2400 mg RYR are much lower than those of the corresponding forms of lovastatin after taking a 20 mg conventional tablet [37]; this is expected to reduce the risk of adverse effects. Similarly to lovastatin, CYP3A4 is involved in the metabolism of monac are substrates of P-glycoprotein. Their bioavailability and safety could t affected by interactions with other medicinal products and foods, although the effects are yet to be fully characterized [29,36]. Plasma concentrations of the h and lactone forms of monacolin K after ingestion of 2400 mg RYR are much those of the corresponding forms of lovastatin after taking a 20 mg convent [37]; this is expected to reduce the risk of adverse effects.
A study in healthy volunteers taking an RYR product reporte pharmacokinetic properties of both forms of monacolin K (lovastatin and lova were linear across the range of 1-4 capsules taken as a single dose, with no accumulation after multiple dosing [36]. Asian ethnicity is associated with a higher statin exposure than in non RYR supplements differ widely in their monacolin K content, resulting in a daily dose range of approximately 0.1-14.5 mg [38][39][40]. This is partly because the relative abundances of monacolin K and other monacolin subtypes in RYR, including monacolins J, L, and X, are affected by the fermentation conditions and yeast strain used during their production [30,39,40]. In addition, RYR contains non-monacolin components, including sugars (25-73% mainly starch), proteins (14-31%), water (2-7%), fatty acids (1-5%), and other bioactive components such as pigments, sterols, isoflavones, and citrinin (discussed below) [5,17]. The contributions of components other than monacolins to the cholesterollowering properties of RYR supplements are difficult to assess due to their varying compositions and very small concentration.
A study in healthy volunteers taking an RYR product reported that the pharmacokinetic properties of both forms of monacolin K (lovastatin and lovastatin acid) were linear across the range of 1-4 capsules taken as a single dose, with no significant accumulation after multiple dosing [36].
Asian ethnicity is associated with a higher statin exposure than in non-Asians at a given dose, partly due to genetically determined differences in transport mechanisms [41]. The approved maximum doses of most statins are therefore lower in some Asian countries (e.g., Japan) than elsewhere [41]. The greater exposure in Asians than Caucasians is more marked for some statins (e.g., rosuvastatin) [42] than for others (e.g., atorvastatin) [43].

RYR versus Placebo and Other Statins Meta-Analyses
A 2021 meta-analysis of 15 high-quality randomized controlled trials (mostly using doses of 600-2400 mg twice daily) involving 1012 subjects showed that RYR significantly decreased LDL-C versus placebo (mean difference [ [11]. An earlier meta-analysis of 20 randomized trials involving 6663 subjects showed that RYR (1200-4800 mg/d) was more effective than a placebo at reducing LDL-C  [10]. Finally, a network meta-analysis of 47 randomized controlled trials involving 4824 subjects, evaluating three different Chinese RYR supplements (most commonly Xuezhikang 600 mg twice daily), showed that RYR significantly reduced LDL-C, TC, and triglycerides versus placebo [67]. No significant differences in the levels of these parameters were observed with RYR versus simvastatin, although a ranking analysis suggested that Xuezhikang (surface under the cumulative ranking [SUCRA] value 82.6%) was more likely than simvastatin (SUCRA value 74.9%) to be effective in reducing LDL-C [67].

Effects of RYR on Inflammatory and Vascular Remodeling Biomarkers and Endothelial Function
Statins have been shown to reduce levels of the inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP) [68], and this is also true of RYR, with reductions in hs-CRP versus placebo observed in subjects with mild hypercholesterolemia (−23.77%, 95% CI −30.54, −17.01) [50] and in those with coronary heart disease (CHD) (−50.0% versus −25.4%, p < 0.05) [46]. Significantly greater reductions in hs-CRP have also been reported for RYR versus simvastatin (p < 0.05) in subjects with unstable angina pectoris and statin-induced elevated liver enzymes [58].
2.6. Beneficial Effects of Exposure to RYR on ASCVD Risk and Events 2.6.1. RYR versus Placebo The effects of RYR compared with placebo on ASCVD risk and events have been evaluated in clinical studies and meta-analyses in varying frail subject populations with a history of MI and/or CHD (Table 4).
In a randomized Chinese study of almost 5000 subjects with a previous MI and average LDL-C levels at baseline, those taking RYR (Xuezhikang) daily for a mean of 4.5 years experienced a lower relative risk of non-fatal MI and death from CHD, ASCVD mortality, and total mortality by 45%, 30%, and 33%, respectively, compared with those taking a placebo [69]. Similar reductions in ASCVD events versus placebo were observed in subgroups from this trial of hypertensive subjects [70] and elderly (aged ≥ 65 years) hypertensive subjects treated with RYR [71].
Meta-analyses in subjects with a history of MI and/or CHD, including those with metabolic syndrome (diabetes or hypertension plus dyslipidemia) showed that, compared with subjects taking a placebo, those taking RYR had a lower risk of ASCVD endpoints including non-fatal MI (risk ratio (RR) 0. 42

RYR versus Other Statins
A real-world, retrospective, population-based cohort study of Taiwan's National Health Insurance Program in individuals without a history of stroke reported a lower risk of stroke in subjects taking RYR than age-and sex-matched controls who received the monacolin K analog lovastatin (hazard ratio [HR] 0.65, 95% CI 0.59, 0.71) [74]. However, hypertension and diabetes were significantly more common in the lovastatin cohort at baseline, which may have increased the baseline risk of stroke in the lovastatin versus RYR cohort [74].
In a comparison of RYR and simvastatin in 90 Chinese subjects with unstable angina pectoris and elevated liver enzymes associated with simvastatin, a significantly lower proportion of subjects receiving RYR or who continued taking simvastatin experienced ASCVD endpoints versus those who stopped taking simvastatin [58].

Beneficial Effects of RYR-Berberine Combinations
In order to lower the dose of RYR and improve tolerability while potentially increasing the cholesterol-lowering effect, combinations of RYR with other nutraceutical compounds that have different lipid-lowering mechanisms of action have been investigated.
In a separate study in 40 subjects with moderate hypercholesterolemia, 6 months' treatment with RYR containing 10 mg monacolins plus 30 mg coenzyme Q10 significantly reduced LDL-C versus placebo (−26.3% versus +3.4%, p < 0.05) [80]. Such combinations also demonstrated improvements compared with placebo in endothelial function assessed via pulse volume displacement (p < 0.05) and arterial stiffness assessed via pulse wave velocity (p < 0.05) in subjects with moderate hypercholesterolemia [79]. The potential benefits of these lipid-lowering and vascular remodeling effects from RYR combinations on CV risks and outcomes remain to be elucidated [76].

Convenience and Preference, and Health Economic Impact
Specific studies relating to the cost-effectiveness, convenience, and patient preference for RYR have not been identified. However, depending on the country, high-quality, highly purified RYR products could cost more than generic statins [5]. Additionally, while lipidlowering drugs may be reimbursed by healthcare systems, the cost of RYR supplements is likely to fall on consumers unless they are classified as medicines, and this may limit their use [9]. Conversely, economic inequalities and geographic location markedly affect the proportion of people who take ASCVD medications, including lipid-lowering drugs [81,82]. For example, one study reported that statin use for secondary prevention was 66.5% in high-income countries compared with only 3.3% in low-income countries [82]. Statin use was also higher in urban versus rural areas within countries (19.9% versus 12% overall; p < 0.0001), with the greatest variation in the lowest-income countries [82]. Thus, RYR may be more easily accessible than pharmacologic interventions in some lower-or middleincome countries.
An additional aspect contributing to preference for RYR is that many individuals experience a real or perceived intolerance to statins [9], often relating to toxicity concerns [83]. Indeed, a key factor related to non-adherence to lipid-lowering drugs in patients with dyslipidemia is presenting with adverse events (AEs) or expressing concerns about them [84]. Adherence to lipid-lowering treatment is also associated with cost, with treatment persistence over 2 years found to be greater for nutraceuticals than for statins in 628 subjects with moderate hypercholesterolemia (odds ratio 1.29, 95% CI 1.14, 1.38) who were fully responsible for paying for treatment [85].

Safety and Tolerability of RYR
A large number of trials of RYR has been carried out on generally healthy mildly hypercholesterolemic subjects, without any evidence of toxicity [86]. The lactone form of monacolin K is structurally identical to lovastatin; it might therefore be expected to produce similar adverse effects to statins. However, numerous studies have shown that RYR is generally well tolerated [5,14]. Statin-related AEs, including AEs leading to discontinuation of therapy, creatine kinase elevation, elevation of liver function tests, and muscle symptoms, have been reported to be dose dependent [87], although the evidence for this relationship in primary prevention is limited [88]. It may therefore be expected that RYR formulations containing a low daily dose of monacolins would be better tolerated than pharmaceutical statins at high doses. However, the lack of standardization and quality control for the preparation of dietary supplements such as RYR, for example in the European Union and the United States, means that the amount of monacolin K and other constituents in RYR supplements, including the mycotoxin by-product of the fermentation process, citrinin, can vary widely [5,89]. In animals, citrinin has nephrotoxic, embryotoxic, and teratogenic effects [89,90], whereas in humans taking RYR, citrinin-related AEs have not been reported. The European Food Safety Authority has determined that citrinin intake should not exceed 0.2 µg/kg body weight/d [91], and good-quality RYR products on the market are certified citrinin free [5,89]. These issues of standardization are common among dietary supplements, with the potential for varying concentrations of active ingredients, substitution of less effective (or ineffective) substances, contamination with pathogens, or the presence of toxic substances [92]. The use of high-quality, purified RYR nutraceuticals produced under good manufacturing practice (GMP) conditions is therefore essential.

Clinical Trials
Overall, RYR has been well tolerated in clinical trials with 4-24 weeks of treatment in diverse populations with dyslipidemia, including those who are intolerant to statins [44,47,49,[51][52][53][54][55]93]. AEs reported in randomized controlled trials have included musculoskeletal, gastrointestinal, hepatic, and general AEs, such as fatigue and dizziness, and laboratory observations such as elevated transaminases, which are rarely serious (Table 5) [44,[47][48][49]51,52,54,55,57,60,63,64,66]. Many of these studies, including those with the greatest numbers of participants, have been conducted in China, and these have shown no increase in the incidence of AEs compared with control groups [73,86]. Despite the higher statin exposure observed for Asian versus non-Asian patients, a large cohort study reported no greater risk of serious AEs in Chinese than in non-Chinese older adults with similar indicators of general health [94].

Meta-Analyses
The low rates of AEs in clinical trials of RYR, as well as short-term follow-up, limited sample sizes, and incomplete reporting of safety in some studies, make meta-analyses of high-quality trials an invaluable source of RYR safety data. Five meta-analyses, including 53,20,12,15, and 22 studies, respectively, concluded that RYR supplements were generally well tolerated, with similar rates of AEs, including musculoskeletal disorders, liver abnormalities, and kidney injury, and serious AEs, as control groups (placebo or other statin) [10,11,76,86,95] (Supplemental Table S3). One of these studies was the metaanalysis of Armolipid Plus ® described above [76]. It concluded that this formulation did not increase the risk of musculoskeletal or gastrointestinal disorders, nor increase aspartate aminotransferase or creatine phosphokinase levels, but was associated with a slight but clinically insignificant increase in alanine aminotransferase compared with placebo [76].

Real-World Evidence
Real-world reports from national surveillance systems provide important information on the safety of RYR-containing supplements, including combinations (Supplemental Table S4).
The Italian Surveillance System of Natural Health Products collected 52 reports containing 55 suspected AEs to RYR-containing dietary supplements [96]. In all except 4 of these reports, the daily dose of monacolin K of the RYR supplements involved was 3 mg. Musculoskeletal and connective tissue (20 reactions [36%]), gastrointestinal (12 [22%]), hepatobiliary (10 [18%]), and skin and subcutaneous tissue disorders (9 [16%]) were the most frequently reported system organ classes (SOCs) for AEs. In 14 reports (27%), the AE was serious, with 13 (25%) requiring hospitalization, notably including 6 of 10 hepatic AEs. One case of rhabdomyolysis was considered certain to be caused by the RYR supplement, while 56% of all reactions were considered probably associated with RYR. The authors concluded that the safety profile of RYR is similar to that of other statins.
A total of 94 reports of 187 suspected AEs to RYR were collected by the Netherlands Pharmacovigilance Centre Lareb [97]. Of the 94 reports, 55 (59%) also involved concomitant medication use. The most frequently reported SOCs were musculoskeletal and connective tissue (64 reactions [34%]) and gastrointestinal disorders (33 [18%]), followed by general (23 [12%]) and nervous system disorders (16 [9%]). Six cases were classified as serious, of which three were acute pancreatitis, two cases had symptoms of rhabdomyolysis, and one case experienced acute hepatic failure. Overall, the role of RYR was considered as certain in two cases: one case of myalgia and one case of abdominal pain.
Of the three reports described above, only the Italian survey describes data on rechallenge, and in only seven subjects [96]. In the absence of rechallenge, the association between RYR and the events reported is unproven.
An additional source of RYR safety data is a post-marketing product-based database for Armolipid ® /Armolipid Plus ® that has collected 542 case reports with 855 AEs [75]. For these RYR products, the daily dose of monacolin K was 3 mg. Based on an estimated 2,287,449 exposed consumers, the rate of AEs was 0.037%, with 26 suspected serious AEs in 21/542 cases (0.0009% of exposed consumers). There are no data on rechallenges.
A real-world retrospective cohort study of Taiwan's National Health Insurance records suggested that RYR use was associated with a decreased risk of incident diabetes versus lovastatin in age-and sex-matched cohorts, with an HR of 0.46 (95% CI 0.43, 0.50) [98].

Discussion
New risk thresholds for pharmacologic treatment in the 2021 ESC guidelines on AS-CVD prevention [2] are reducing the eligibility for statins of apparently healthy individuals with mild-to-moderate hypercholesterolemia [99]. Estimating the effect of RYR on the risk of ASCVD events in a primary prevention population, who are generally relatively young and healthy, may be misleading with current risk calculators, which are dominated by age and focus on 10-year risk. Instead, the rationale for using RYR is to provide a reduction in LDL-C that, although numerically modest, may be achieved for decades with habitual use. This has the potential to reduce the lifetime ASCVD risk [25]. In a recent network meta-analysis [100], RYR demonstrated a positive effect on LDL-C compared with commonly used lipid-lowering nutraceuticals (for instance phytosterols). RYR also has the advantage that it can be consumed once daily compared with other natural compounds such as artichoke extracts or bergamot polyphenols.
RYR provides lipid-lowering effects similar to those of low-dose, low-intensity statins [10,11] in subjects with mild-to-moderate hypercholesterolemia, with clinical-trial and real-world data demonstrating a favorable safety and tolerability profile similar to that of other statins [10,11,75,96]. Significant reductions of LDL-C have been reported with formulations containing doses of monacolin K as low as 2-3 mg/day [53,55,59,60], at which the risk of AEs can be expected to be low. Other AEs have been reported for RYR supplements containing higher doses of monacolin K than the supplements usually approved for use in Europe and elsewhere, and also for supplements with unknown RYR quality where the lack of rechallenge casts doubt on the cause-event relationship.
Clinical trials have shown that RYR is effective and well tolerated in patients intolerant to statins [48,58,60,93], and the International Lipid Expert Panel provides a class IA recommendation for RYR in this setting [13,14]. In patients with an indication for statin therapy, it is important to continue treatment because discontinuation is associated with an increase in cardiovascular events [83]. Strategies for resumption or continuation of therapy include reduction in the dose (or dose frequency, e.g., alternate-day dosing) or switching to a different statin [83,101,102]. The use of RYR containing a low dose of monacolin K could be a logical alternative to a conventional statin for such patients. RYR, being a food supplement, may be less vulnerable to the "nocebo" effect-a perception of AEs resulting from an expectation of harm-than a pharmaceutical preparation.

Conclusions
RYR is an option for lowering LDL-C levels in individuals with mild-to-moderate hypercholesterolemia who are not eligible for pharmacologic treatment, particularly those who are unable to implement lifestyle modifications, and also for individuals who are intolerant to statins or who prefer to take a nutraceutical rather than a pharmacologic product. Given the large number of RYR nutraceutical products available and the limited regulatory oversight in some countries, physicians and recipients should choose a highquality, purified RYR nutraceutical with a suitably low dose of monacolin K, produced under good manufacturing practice (GMP) conditions that is certified citrinin free. This will ensure consistent monacolin K dosing, help to reduce the risk of side effects, and minimize potential AEs due to contaminants. In the future, further studies will help to define the place of RYR in the management of dyslipidemia. For example, the role of components of RYR other than monacolins in lipid-lowering effects and their interactions with monacolin K, require further investigation, and a trial comparing an RYR preparation with a pharmaceutical containing the same dose of lovastatin could be informative [103]. Combinations of other nutraceuticals with RYR also require further clinical trials to establish the risk-benefit ratios and cost-effectiveness of these options. For patients with mild hypercholesterolemia who cannot tolerate statins and related products, ranges of alternative natural products are being investigated. Compounds derived from Protium heptaphyllum gum resin, belonging mainly to the ursane, oleanane, and tirucallane groups, have been shown to reduce cholesterol production and regulate the expression of proteins involved in their metabolism in human hepatocytes [31]. Herbs including basil, thyme, and sage contain lutein, zeaxanthin, vitamin E, and various polyphenols and have antioxidant activity [104]. Fruits including pomegranate and apricot contain various ingredients, including phenolic compounds, anthocyanins, and vitamins A, C, and E, with antioxidant and free radical scavenging actions, which may be more potent when they act in combination [105,106]. Omega-3 fatty acids are abundant in fish oils and marine microorganisms, peptides extracted from fish have cholesterol-reducing actions, and carotenoids and phenolic compounds with antioxidant activity have been derived from crustaceans and seaweeds [107]. The current evidence, however, shows that RYR delivers a modestly effective dose of monacolin K, and has other components that may add to the benefits of treatment.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/nu15102288/s1, Table S1. Other components of monacolin K formulation in key randomized controlled trials of RYR versus placebo or statins in subjects with dyslipidemia; Table S2. Summary of serum lipid outcomes in key randomized controlled trials of RYR versus placebo or statins in subjects with dyslipidemia; Table S3. Summary of RYR safety reported by meta-analyses; Table S4. Summary of RYR adverse drug reaction reports collected by surveillance systems.
Author Contributions: A.F.G.C. conceived the original idea for this article. All authors searched and reviewed the literature, agreed on the references to be included, interpreted the results, and contributed to planning, writing, and editing the manuscript. All authors critically revised the manuscript drafts. All authors have read and agreed to the published version of the manuscript.
Funding: Medical writing assistance was provided by Gail Rickard, PhD, and Richard Murphy, PhD (Adelphi Communications Limited, Macclesfield, UK), and was funded by Viatris Inc., Monza, Italy.
Institutional Review Board Statement: Not applicable to this type of study.
Informed Consent Statement: Not applicable to this type of study.
Data Availability Statement: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.