The following are key points to remember from this article on the role of nutraceuticals in statin-intolerant patients:

1. The aim of this expert opinion paper is to provide the first attempt at recommendation on the management of statin intolerance through the use of nutraceuticals with particular attention on those with effective low-density lipoprotein cholesterol (LDL-C) reduction using level of evidence and classes of recommendation.
2. Due to statin-associated muscle symptoms (SAMS), adherence to statin therapy is troubling. Nutraceuticals, such as red yeast rice, bergamot, berberine, artichoke, soluble fiber, and plant sterols and stanols alone or in combination with each other, as well as with ezetimibe, might be considered as an alternative or add-on therapy to statins.
3. Although there is still insufficient evidence, nutraceuticals could exert significant lipid-lowering activity and might have non–lipid-lowering actions, including improvement of endothelial dysfunction and arterial stiffness, as well as anti-inflammatory and antioxidative properties.
4. The Canadian Consensus Working Group Update defined statin intolerance as a clinical syndrome, not caused by drug interactions or risk factors for untreated intolerance and characterized by significant symptoms and/or biomarker abnormalities that prevent the long-term use and adherence to statins documented by challenge/ de-challenge/ re-challenge, using ≥2 statins, including atorvastatin and rosuvastatin, and that leads to failure of maintenance of therapeutic goals, as defined by national guidelines.
5. In the case of SAMS, it is advisable to change the dose (and add nonstatin drugs), change the statin preparation, or try alternate day statin therapy, or if SAMS are associated with all statins even at the lowest dose, then nonstatin drugs (ezetimibe, fibrates, proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors, and niacin if available) and certain nutraceuticals might be considered as alternatives for lipid lowering.
6. The role of nutraceuticals in statin-intolerant subjects varies by the degree of cardiovascular risk as determined by 10-year risk predictors (high or intermediate), the degree of statin intolerance (partial or complete), and the LDL-C target not reached with the tolerable statin and/or nonstatin therapy.
7. Each of the nutraceuticals recommended is available in concentrated pill or powder formulation. Dose and effects are summarized in the following table:

Product	Class/Level	Dose	LDL-C Lowering Ranges (mean mg/dl or %)
Artichoke	IIa / B	1800 mg/d	11-23%
Berberine	I / A	300 mg/d	25 mg/dl, 24%
Bergamot	IIa / B	1300 mg/d	61 mg/dl
Fibers	IIa / A	3-20 g/d	Up to 20%
Garlic	IIa / A	5-6 g/d	9 mg/dl, 20%
Green tea	IIa / A	170-1200 mg/d	7.4 mg/dl
Lupin	IIa / A	25 g/d	4-12%
Plant stanols and sterols	IIa / A	1-3.0 g/d	12 mg/dl, 16%
PUFAs	I / A	1-5 g EPA/DHA/d	Primarily triglycerides
Red yeast rice	I / A	1200-4800 mg/d	36-91 mg/dl
Spirulina	IIa / A	1-10 g/d	41.3 mg/dl
Soy protein	IIa / A	35 mg/d-25 g/d	<5 mg/dl

Perspective:

The authors recognize the limitation of nonstatin studies, which are each inadequately powered for both safety and efficacy. It should be noted that the nutraceuticals are expensive and the standardization for dosing and quality is not available for most. They included some with small studies demonstrating nonlipid vascular and anti-inflammatory effects, which have been shown to have little predictive value of benefit. As a lipid specialist, I have tried several of these products in statin-intolerant patients, and other than red yeast rice and stanols, they have been disappointing. This is not the case with bile resins and ezetimibe. I am concerned that the publication of this review will encourage the use of these and other unproven products by patients who would rather take ‘natural roots and herbs’ than pharmaceuticals with well-established risk and benefit data in coronary and other atherosclerotic vascular disease.

Keywords: Antioxidants, Berberine, Biomarkers, Cholesterol, LDL, Consensus, Dietary Supplements, Dyslipidemias, Fatty Acids, Omega-3, Fibric Acids, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipids, Niacin, Primary Prevention, Risk Factors, Subtilisins, Vascular Diseases, Vascular Stiffness

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