Does EFSA statement on Monacolin content of nutraceutical combinations impair their lipid lowering effect? The LopiGLIK experience

Abstract

Background

Monacolin-K, the active component of red yeast rice (RYR), reduces cholesterol by inhibiting HMG-CoA reductase. Following safety concerns, the European Food Safety Authority (EFSA) recommended limiting Monacolin-K intake to less than 3 mg/day due to adverse effects at higher doses.

Case presentation

: A study comparing Armolipid Plus^® and LopiGLIK^® found LopiGLIK^® more effective in lowering LDL cholesterol, possibly due to slightly higher dosages of Berberine and Monacolin-K. Despite reducing Monacolin-K content to 2.99 mg following EFSA guidelines, LopiGLIK^® maintained its cholesterol-lowering efficacy.

Conclusions

Taken together, our results indicate that other ingredients, such as Morus alba, may contribute to LopiGLIK^®’s enhanced effectiveness, challenging the notion that minor differences in Monacolin-K dosage account for the observed efficacy.

Background

Monacolin-K (also known as Lovastatin) is the major active component of red yeast rice (RYR), which is produced by the fermentation of white rice and the mold fungus Monascus purpureus. By inhibiting the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, Monacolin-K has been shown to be effective in reducing serum cholesterol levels [1].

However, in 2018, following a request from the European Commission to the European Food Safety Authority (EFSA), the Scientific Panel on Food Additives and Nutrient Sources added to Food (ANS) was asked to provide a scientific opinion on the safety of Monacolin-K from RYR [2]. This risk assessment was carried out to implement Article 8.2 of European Regulation N.1925/2006 on the addition of vitamins, minerals, and certain other substances to foods, for Monacolin-K from RYR; this Article is referring to a possible prohibition, restriction, or Community scrutiny of a substance or ingredient by placement in Annex III, Part A, B or C of this Regulation. The Panel was provided with post-marketing data related to certain food supplements containing Monacolin-K from RYR with daily recommended intake ranging from 10 to 20 mg/day. Eighty case reports encompassing 142 adverse reactions were collected. Most of them were reported under the ‘system organ classes ’Gastrointestinal disorders’ (24%), followed by ‘Musculoskeletal and connective tissue disorders’ (15%), and ‘Nervous system disorders’ (15%). Eight cases involved 13 serious adverse events (arrhythmia, seizure, splegia, oropharyngeal discomfort, pharyngeal erosion, abdominal pain, impaired gastric emptying, respiratory distress, hepatitis acute, abdominal discomfort, dyspepsia, toxic epidermal necrolysis, hepatitis) [2]. All these serious cases were spontaneous and six of them were medically confirmed; among the latter cases, confounding factors such as advanced age and/or concomitant medication were reported in three cases; two of these patients recovered after withdrawn of the product while the outcome is unknown for the remaining case. Little information is available for the remaining three serious medically confirmed cases [2]. Patients involved in the two serious non-medically confirmed cases fully recovered after product withdrawal [2]. The Panel considered that the available information on the adverse effects reported in humans were sufficient to conclude that Monacolin-K from RYR when used as food supplements was of significant safety concern at the use level of 10 mg/day. The Panel further considered that individual cases of severe adverse reactions had been reported for Monacolin-K from RYR at intake levels as low as 3 mg/day. On these grounds, the EFSA recommended the maximum dosage of Monacolin-K supplementation by RYR to be < 3 mg/day.

Case presentation

In 2017, our group published the results of a randomized and multicenter study comparing the effect of Armolipid Plus^® versus that of LopiGLIK^® on lipid levels in subjects with mild hypercholesterolemia [3]. The composition of these nutraceuticals is reported below; Armolipid Plus^®: Policosanol (10 mg), Red yeast rice (RYR, 200 mg, of which 3 mg Monacolin-K), Berberine (500 mg), Astaxanthine (0.5 mg), Folic acid (200 mcg) and Coenzyme Q10 (2 mg); LopiGLIK^®: Berberine (531 mg), RYR powder (220 mg, of which 3.3 mg Monacolin-K), Morus alba (200 mg). Data from an overall sample of 359 adults were reported [3]: 72% of subjects treated with LopiGLIK^® and 43% treated with Armolipid Plus^® achieved the primary endpoint, i.e. therapeutic targets of LDL cholesterol (LDL-C) < 130 mg/dl. Both treatments reduced plasma levels of total and LDL-C and triglycerides (p < 0.001 for all comparisons). The treatments also reduced systolic and diastolic blood pressure, plasma levels of glycated hemoglobin, insulin and HOMA index [3]. The changes induced by LopiGLIK^® in all these metabolic parameters were greater than those obtained with Armolipid Plus^® [3]. These data, while confirming the well-known lipid lowering effect of Armolipid Plus^® [4, 5] indicate that LopiGLIK^® is more effective in achieving the primary endpoint. LopiGLIK^® normalized LDL-C (LDL-C < 130 mg/ml) in 72% of the population vs. 43% in the Armolipid Plus^® arm; LopiGLIK^® also caused a significantly greater reduction than Armolipid Plus^® in Total-C, LDL-C and triglyceride levels. This effect of LopiGLIK^® on TC-C, LDL-C and TG levels were quite consistent with data from a pilot study [6]. One of the hypotheses posited to justify the difference detected between the effects of the two treatments was the small increases in the dosage of Berberine (531 vs. 500 mg) and Monacolin-K (3,3 vs. 3 mg) LopiGLIK^® vs. Armolipid Plus^®.

Based on the recent EFSA recommendations [2], the LopiGLIK^® formula was modified and its Monacolin-K content was reduced to 2.99 mg. However, to our knowledge, there is no clinical evaluation of the effects of this new formula on lipid and glucose metabolism. In order to clarify this issue, we analyzed the data of the patients followed in the Outpatient Clinic of the Hypertension Center of the “Federico II” University of Naples, Italy who participated in the original trial [3]. Of note, patients that had been randomized to the LopiGLIK^® arm are still on treatment with its modified formula. Thus, we compared the values of serum concentration of glucose, triglycerides, total, LDL, and HDL cholesterol at baseline, during the treatment with the nutraceutical combination containing 3.3 mg of Monacolin-K, and during treatment with the 2.99 mg Monacolin-K concentration formula of the same combination. Table 1 shows the results obtained in a population of 13 patients (mean age 64.5 ± 7.3 years, 6 men and 7 women). Our results demonstrate that the reduction in Monacolin-K content does not modify the cholesterol lowering effect of LopiGLIK^®, since there was a comparable reduction of the total and LDL-cholesterol during the two treatment periods.

Table 1 Effects of two different formulations of LopiGLIK^® on glycemia and serum lipids

Discussion and conclusions

In conclusion, our data rule out the hypothesis that the magnitude of the difference in the reduction of total and LDL cholesterol serum concentrations in the groups treated with Armolipid Plus^® or LopiGLIK^® treatments may be accounted for by the small increases in the dosage of Monacolin-K (3,3 vs. 2.99 mg) and allow the speculation that the presence of other components, such as Morus alba, may contribute to the enhanced cholesterol lowering action of LopiGLIK^®.