Nutraceuticals may offer a solution to patients who cannot tolerate statins because of severe muscle pain. Emerging evidence shows that red yeast rice (RYR), bergamot, berberine, artichoke, soluble fiber, and plant stanols and sterols as monotherapy or adjunctive therapy may offer an alternative, along with ezetimibe, to prevent cardiovascular events by lowering low-density lipoprotein-cholesterol (LDL-C).1 Other pleiotropic effects of nutraceuticals may improve arterial stiffness and endothelial dysfunction and may provide antioxidant and anti-inflammatory effects.2
“The lower rate of muscle pain with nutraceuticals than with statins depends on some aspects such as dosage, combination regimens, and purification,” explained Arrigo FG Cicero, MD, PhD, president of the Italian Nutraceutical Society and researcher in the atherosclerosis and metabolic disease research unit at the University of Bologna in Italy. “If RYR is used, the higher-dosed products have the same probability of side effects as statins, because the mechanism of action is the same. The use of combined nutraceuticals with different mechanisms of action reduces the risk for side effects related to higher dosages of single products. The degree of purification is also important. Highly standardized products are preferable, because they reduce the risk for contamination and side effects.”
What Is Statin Intolerance?
Although pivotal trials of statins showed that adverse events were few and minor, clinical evidence has shown otherwise.3 Among patients taking statins, the chief complaint is muscle pain. As a result, many discontinue taking statins altogether or decrease the dose, which can lead to a risk for cardiovascular events and increased healthcare costs.3 Compared with adherent Medicare beneficiaries, those who claimed to be statin intolerant had a higher risk for recurrent myocardial infarction (hazard ratio [HR] 1.50; 95% CI, 1.30-1.73) and coronary heart disease events (HR 1.51; 95% CI, 1.34-1.70).3
To clarify what patients mean when they complain about statins, cardiologists and other lipid experts attempted to define statin-associated muscle symptoms (SAMS).3 There is no one SAMS definition; however, most experts agree that patients need to be intolerant to at least 2 statins and not have reached lipid-lowering goals.3 Lipid expert groups also suggest examining any drug-drug interactions or comorbidities that may contribute to the muscle symptom complaints. Experts agree that a patient does not have SAMS when symptoms3:
· Abruptly begin or stop when statins are started or discontinued
· Do not improve even after statins have been discontinued for 12 weeks
· Occur after >12 weeks of statin use
· Occur with other non-statin lipid-lowering agents
The SAMS Clinical Index (SAMS-CI) is a 4-question survey that may help clinicians ascertain whether patients’ complaints are indeed SAMS.3 Although the index has not been validated, in one study a score of 4 or less was 91% predictive of not having SAMS.3 Other potential but not yet validated tests to diagnose SAMS include the rs4149056 variant in the SLCO1B1 gene, increases in creatinine kinase level, and the presence of hydroxy-methylglutaryl coenzyme A reductase autoantibodies.3
With the SAMS-CI, clinicians can systematically evaluate muscle symptoms as well as “associated adverse events — hypothyroidism, very low vitamin D levels, and drug-drug interactions,” explained cardiologist Robert S. Rosenson, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai in New York City. “This approach begins with assessment, screening for secondary disorders and drug interactions followed by a change to another statin, dose reduction of the statin, alternate-day statin therapy, and possibly nutraceuticals.”
Combination Therapy May Boost Statin Efficacy
In a parallel 3-arm, double-blind trial, Cicero and colleagues compared the lipid-lowering effects of phytosterols, RYR, and a combination of the 2 nutraceuticals.4 The first group was given 800 mg of phytosterols (n=20), the second group received 5 mg of monacolins in RYR (n=22), and the third group received a combination of the 2 (n=23).4
At the end of the 8-week study, patients in the phytosterol had no significant decrease in LDL level. However, patients in the RYR group showed a significant decrease in both LDL-C (-20.5% vs baseline) and apolipoprotein B (-14.4% vs baseline; both P <.001). Patients who received combination therapy had even greater reductions in LDL-C vs baseline (-23.0%) and apolipoprotein B vs baseline (-19.0%; both P <.001).4
Nutraceuticals Are Not Risk Free
There are some caveats to consider before introducing nutraceuticals into a lipid-lowering regimen. The evidence base does not yet include long-term safety or efficacy data that confirm nutraceuticals’ benefit in reducing cardiovascular disease morbidity and mortality.1
The US Food and Drug Administration regards supplements such as RYR as a drug if they contain more than trace elements of the active ingredient monacolin K.5 Purity is also difficult to assess, so clinicians and consumers may not know whether a supplement like RYR contains harmful contaminants such as citrinin.5
“Not all therapies that lower LDL-C have been shown to reduce atherosclerotic cardiovascular events,” cautioned Dr Rosenson. “Several examples include estrogen replacement therapy in postmenopausal women and cholesteryl ester transfer protein inhibitors.”
“Undoubtedly, the lipid-lowering nutraceuticals do not have the same efficacy as statins, and their preventive effects have been demonstrated only on surrogate markers of cardiovascular disease (eg, inflammatory biomarkers or instrumental biomarkers such as flow-mediated dilation or pulse wave velocity),” added Dr Cicero. “We have already demonstrated that patients are more persistent in treatment with nutraceuticals than with statins.”6
Summary & Clinical Applicability
Although statins have proven efficacious in reducing cardiovascular events, not every patient can tolerate them because of severe muscle pain. International experts have demonstrated that nutraceuticals in combination with statins or monotherapy can help some statin-intolerant patients achieve their lipid goals.
Limitations & Disclosures
1. Banach M, Patti AM, Giglio RV, et al, for the International Lipid Expert Panel (ILEP). The role of nutraceuticals in statin intolerant patients. J Am Coll Cardiol. 2018;72(1):96-118.
2. Cicero AFG, Colletti A, Bajraktari G, et al. Lipid-lowering nutraceuticals in clinical practice: position paper from an International Lipid Expert Panel. Nutr Rev. 2017;75(9):731-767.
3. Rosenson RS, Baker S, Banach M, et al. Optimizing cholesterol treatment in patients with muscle complaints. J Am Coll Cardiol. 2017;70(10):1290-1301.
4. Cicero AFG, Fogacci F, Rosticci M, et al. Effect of a short-term dietary supplementation with phytosterols, red yeast rice or both on lipid pattern in moderately hypercholesterolemic subjects: a three-arm, double-blind, randomized clinical trial. Nutr Metab (Lond). 2017;14:61.
5. National Center for Complementary and Integrative Health. Red Yeast Rice. https://nccih.nih.gov/health/redyeastrice. Updated July 2013. Accessed August 13, 2018.
6. Cicero AFG, Derosa G, Parini A, Baronio C, Borghi C. Factors associated with 2-year persistence in fully non reimbursed lipid-lowering treatments. Atherosclerosis. 2014;235(1):81-83.