Safety and Efficacy of Red Yeast Rice Phytocomplex and Lovastatin: a Comparative Analysis

In the last 20 years, the demand for red yeast rice-based food supplements has significantly increased as consumers have been looked for natural alternatives to manage blood cholesterol levels without the adverse effects associated with synthetic statins. Actually, monacolin K, derived from red yeast rice (RYR) and chemically identical to lovastatin, inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, offering a natural alternative to synthetic drugs. In 2018, despite the health claim approved in 2011, the European Food Safety Authority (EFSA) raised concerns about the safety of monacolin K consumption, especially for vulnerable populations, and highlighted the lack of knowledge on RYR phytocomplex. Consequently, in 2021, the European Commission established a new maximum intake limit < 2.99 mg/day for monacolins. This study aimed to investigate the safety and efficacy of RYR phytocomplex compared to the sole monacolin K (=lovastatin) by analyzing eight different RYR samples with different monacolin K and secondary monacolins content. Efficacy was evaluated through a validated cell-free enzymatic assay, while an integrated in vitro simulated digestion and in silico ADME prediction were employed to compare the pharmacokinetics of different samples and lovastatin. The safety of RYR was assessed by monitoring cytotoxicity in intestinal, hepatic, kidney, and skeletal muscle cells using cell viability assays. Furthermore, muscle damage-related targets and myokines were measured by qRT-PCR in myoblasts exposed to prolonged non-toxic stimuli. Results demonstrated that RYR samples have a large chemical variability not only related to monacolin K content, in lactone and hydroxy-acid form, but also as regards pigments, secondary monacolins, polyphenols, and triterpenes. The enzymatic test revealed that all samples were more effective in inhibiting HMG-CoA activity than lovastatin at equivalent monacolin K content. Although secondary monacolins had a weaker effect than monacolin K, a synergistic effect was observed within the phytocomplex. Additionally, the phytocomplex facilitated higher bioaccessibility of monacolin K in RYR compared to lovastatin. Regarding cell viability, lovastatin and RYR samples exhibited no toxic effects up to 150 g/mL on intestinal, hepatic, and kidney cells; however, variable effects were observed on skeletal muscle cells at medium-high concentrations. Nevertheless, at physiological non-toxic concentrations, RYR samples did not impact the expression levels of myokine IL-6, autophagy factors, and catabolic markers of protein balance, unlike synthetic statin. These results suggest that RYR and lovastatin share similar biological activities, but the phytocomplex's contribution from secondary monacolins, pigments, polyphenols, and triterpenes ensure a superior safety profile for this botanical food supplement. However, it is important to note that the composition of RYR phytocomplex can vary significantly between different products on the market. This variability highlights the need for standardization and quality control measures to ensure the safety and efficacy of this botanical food supplement. In conclusion, our study provides evidence supporting the enhanced efficacy, bioaccessibility, and safety profile of RYR phytocomplex compared to lovastatin demonstrating its potential as a natural and effective option for hypercholesterolemia management.