Usefulness of Low-Dose Statin Plus Ezetimibe and/or Nutraceuticals in Patients With Coronary Artery Disease Intolerant to High-Dose Statin Treatment

doi:10.1016/j.amjcard.2018.09.041

The American Journal of Cardiology

Volume 123, Issue 2, 15 January 2019, Pages 233-238

https://doi.org/10.1016/j.amjcard.2018.09.041 Get rights and content

High-dose statin (HDS) therapy is recommended to reduce low-density lipoprotein cholesterol (LDL-C); however, some patients are unable to tolerate the associated side effects. Nutraceuticals have shown efficacy in lowering LDL-C. The aim of this study was to evaluate whether the combination of low-dose statin (LDS) plus ezetimibe (EZE) or LDS plus nutraceutical (Armolipid Plus [ALP] containing red yeast rice, policosanol, and berberine) can lead to a higher proportion of high-risk patients achieving target LDL-C. A secondary objective was to assess the efficacy of triple combination LDS + EZE + ALP in resistant patients (LDL-C >70 mg/dl). A randomized, prospective, parallel-group, single-blind study was conducted in patients with coronary artery disease (n = 100) who had undergone percutaneous coronary intervention in the preceding 12 months, were HDS-intolerant, and were not at LDL-C target (<70 mg/dl) with LDS alone. Patients received either LDS + EZE or LDS + ALP. Of the 100 patients, 33 patients (66%) treated with LDS + EZE and 31 patients (62%) treated with LDS + ALP achieved target LDL-C after 3 months, which was maintained at 6 months. Patients who did not achieve the therapeutic goal received a triple combination of LDS + EZE + ALP for a further 3 months. At 6 months, 28 of 36 patients (78%) achieved LDL-C target. Overall, 92% of patients enrolled in this study were at target LDL-C at 6 months. No patients in any group experienced major side effects. In conclusion, in HDS-intolerant coronary artery disease patients, the combination of LDS plus EZE and/or ALP represents a valuable therapeutic option allowing most patients to reach target LDL-C within 3 to 6 months.

Section snippets

Methods

This was a randomized, prospective, parallel group, and single-blind trial of LDS, EZE, and ALP in HDS-intolerant CAD patients (Target ChOlesterol; TACO). Patients were consecutively enrolled from October 1, 2017 until December 21, 2017 (ClinicalTrials.gov identifier: NCT03277079). The nutraceutical used in this trial was ALP a formulation of 6 naturally occurring plant extracts which contains 3 naturally occurring substances with putative complementary lipid-lowering properties: red yeast rice

Results

One hundred patients with CAD were enrolled consecutively in the study (mean age 61 years; 55% male), among whom 30% had an acute coronary syndrome. Patients were treated with LDS and randomized to receive either EZE or ALP. Baseline clinical features and lipid profiles were similar between groups (Table 1).

The statin therapies most frequently taken by patients were simvastatin 20 mg and atorvastatin 20 mg (Table 2). The flow of patients through the study is presented in Figure 1.

After 3

Discussion

In this study, we assessed the effects of the nutraceutical combination ALP and EZE in addition to LDS therapy in patients with CAD and previous PCI. We found that dual therapy with either LDS plus EZE or ALP allowed more than 60% of patients to achieve the therapeutic target for lowering LDL-C concentration (<70 mg/dl) by 3 months (66% and 62%, respectively). Although there was no significant difference between groups for the proportion of patients who achieved target LDL-C at 3 months,

Disclosures

The authors have no conflicts of interest to disclose.

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Red yeast rice (RYR) is an entirely natural product that originates from the fermentation of white rice (Oryza sativa) with a yeast, mainly Monascus Purpureus, and has been part of traditional Chinese medicine and diet since ancient times. It has generated great interest in recent years in the context of cardiovascular (CV) prevention due to its ability to inhibit endogenous cholesterol production, helping to achieve and maintain optimal plasma lipid concentrations. This review aims to make an extensive 360-degree assessment and summary of the whole currently available scientific evidence about RYR, starting with its biochemical composition, passing through a historical reconstruction of all the studies that have evaluated its efficacy and safety in cholesterol-lowering action, with a focus on CV outcomes, and ultimately addressing its other relevant clinical effects. We also discuss its possible therapeutic role, alone or in combination with other nutraceuticals, in different clinical scenarios, taking into account the positions of major scientific documents on the issue, and describe the articulate legal controversies that have characterized the regulation of its use up to the present day. RYR preparations have been proven safe and effective in improving lipid profile, with a potential role in reducing cardiovascular risk. They can be considered as additional supportive agents in the armamentarium of lipid-modifying therapies.
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Para el tratamiento de la hipercolesterolemia, además de aconsejar una alimentación saludable, puede ser conveniente recomendar alimentos funcionales o nutracéuticos con efecto hipolipemiante. Dado el progresivo incremento en el número de estos productos y su creciente utilización por la población, la Sociedad Española de Arteriosclerosis (SEA) ha creído conveniente revisar la información disponible, seleccionar los resultados de los estudios científicamente más sólidos y posicionarse sobre la utilidad de los mismos, para recomendar a los profesionales sanitarios y a la población general su potencial utilidad en términos de eficacia y sus posibles beneficios y limitaciones. Se han identificado los siguientes escenarios clínicos en los que se podrían utilizar estos productos y que se analizarán con más detalle en este documento: 1. Tratamiento hipolipemiante en sujetos con intolerancia a estatinas. 2. Tratamiento hipolipemiante «a la carta» en personas en prevención primaria. 3. Prevención cardiovascular a largo plazo en personas sin indicación de tratamiento hipolipemiante. 4. Pacientes con tratamiento hipolipemiante optimizado que no alcanzan objetivos terapéuticos.
In the management of hypercholesterolemia, besides advising a healthy, plant-based diet, it may be useful to recommend functional foods or nutraceutical with cholesterol-lowering properties. Given the progressive increase in the number of these products and their rising use by the population, the Spanish Society of Arteriosclerosis (SEA) has considered it appropriate to review the available information, select the results of the scientifically more robust studies and take a position on their usefulness, to recommend to health professionals and the general population their potential utility in terms of efficacy and their possible benefits and limitations. The following clinical scenarios have been identified in which these products could be used and will be analyzed in more detail in this document: (1) Hypolipidemic treatment in subjects with statin intolerance. (2) Hypolipidemic treatment «a la carte» in individuals in primary prevention. (3) Long-term cardiovascular prevention in individuals with no indication for lipid-lowering therapy. (4) Patients with optimized lipid-lowering treatment who do not achieve therapeutic objectives.
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Citation Excerpt :
These improvements appeared to be maintained in the long-term observation (20). The RYR-berberine association has also been tested in association with ezetimibe in statin-intolerant patients, reaching LDL-C reduction of approximately 35% and TG reduction of approximately 25% (21), as compared with baseline, which is similar to what has been reported for moderate-intensity statins from the European Society of Cardiology/European Atherosclerosis Society 2019 guidelines (11). Of some interest is also the combination of RYR with plant sterols or artichoke extracts.
The extracts of red yeast rice (RYR) are currently the most effective cholesterol-lowering nutraceuticals. This activity is mainly due to monacolin K, a weak reversible inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, whose daily consumption causes a reduction in low-density lipoprotein (LDL)-cholesterol plasma levels up to 15% to 25% within 6 to 8 weeks. The decrease in LDL-cholesterol is accompanied by a proportional decrease in total and non–high-density lipoprotein cholesterol, plasma apolipoprotein B, and high-sensitivity C-reactive protein. Some trials suggest that RYR use is associated with improvement in endothelial function and arterial stiffness, whereas a long-term study supports its role in the prevention of cardiovascular events. Despite the statin-like mechanism of action, the risk related to 3 to 10 mg monacolin K taken per day is minimal (mild myalgia in previously severely statin-intolerant subjects). RYR could represent a therapeutic tool to support lifestyle improvement in managing mild to moderate hypercholesterolemia in low-risk patients, including those who cannot be treated with statins or other LDL-cholesterol–lowering therapies.
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: Funding: This work was supported by the Italian Ministry of Education, University and Research, italy. The National Operational Program (PON) for Research and Competitiveness is co-funded with the European Regional Development Fund (ERDF) and national resources. It promotes initiatives and projects for scientific research and industrial competitiveness, grantnumber PON03PE_00078.

: TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT03277079.

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Usefulness of Low-Dose Statin Plus Ezetimibe and/or Nutraceuticals in Patients With Coronary Artery Disease Intolerant to High-Dose Statin Treatment

Section snippets

Methods

Results

Discussion

Disclosures

Eur J Intern Med

Atheroscler Suppl

Pharmacol Res

Am J Cardiol

Am J Cardiol

Nutr Metab Cardiovasc Dis

Arch Med Res

Atherosclerosis

Am J Med Sci

Adherence to statin therapy and LDL cholesterol goal attainment by patients with diabetes and dyslipidemia

Diabetes Care

Eur Heart J

Nutraceuticals in the management of patients with statin-associated muscle symptoms, with a note on real-world experience

Clin Cardiol

Recent perspectives on the role of nutraceuticals as cholesterol-lowering agents

Curr Opin Lipidol