Phytosterols, Red Yeast Rice, and Lifestyle Changes Instead of Statins

A Randomized, Double-Blinded, Placebo-Controlled Trial

David J. Becker, MD; Benjamin French, PhD; Patti B. Morris, RD; Erin Silvent, BA; Ram Y. Gordon, MD

Disclosures

Am Heart J. 2013;166(1):187-196. 

In This Article

Discussion

Our study compared the lipid-lowering efficacy of phytosterol tablets vs placebo and lifestyle changes vs usual care in patients taking RYR who were statin intolerant or refused statin therapy. Phytosterol tablets did not significantly improve lipoprotein levels at any period compared with placebo. Participants in the LCG were 2.3 times more likely to achieve an LDL-C <100 mg/dL and had significantly more weight loss than the UCG. All participants were treated with RYR and LDL-C, TC, TG, and CRP decreased significantly during the study.

Some patients in clinical practice refuse to take statins. Others stop statin therapy because of adverse effects, most commonly SAMs, which occur in up to 10% of patients[13] and may affect 1.3 million Americans.[14] Treatment of hyperlidemia without statins is challenging. Recent, well-publicized negative trials regarding ezetimibe, fenofibrate, and niacin have further confused the issue.[15–17] Some patients who refuse or stop statin therapy adopt alternative therapies including phytosterols and RYR. In 2008, the global market for phytosterols was $555 to 585 million;[18] in 2009, Americans spent more than $20 million on RYR.[19]

In our study, phytosterol tablets did not lower LDL-C or demonstrate a beneficial effect on other lipoproteins or hs-CRP. Participants took 1.88 g of bioactive phytosterol tablets in 2 divided doses, equivalent to the published therapeutic dose,[5,20] and the composition was confirmed by an independent laboratory (online Appendix Supplementary Table II). The lack of effect of the phytosterol tablets is puzzling because other trials have demonstrated up to 15% LDL-C lowering with phytosterol consumption.[6] We chose phytosterols in tablet form to improve compliance and to blind phytosterols vs placebo. However, our results may have been different if we had used phytosterols in a different form, such as margarine, or had used a plant stanol instead of a sterol tablet. One study showed a lack of a sustained LDL-C–lowering effect of phytosterols as opposed to stanols.[21] It is also possible that RYR may have negatively interacted with the phytosterol tablets, which were taken concomitantly. Nonetheless, compliance was excellent for the yearlong trial for both phytosterol tablets and placebo (online Appendix Supplementary Table IV), and we showed no significant LDL-C–lowering effects of a popular form of phytosterol supplement, compared with placebo, when taken on top of RYR therapy.

Our trial highlights a growing controversy about the widespread consumption of phytosterols in enhanced foods and supplements. Despite the Adult Treatment Panel III recommendation that "2 g/day of plant stanols/sterols are a therapeutic option to enhance LDL-C,"[22] there are no data that phytosterols reduce the risk of cardiovascular events.[23,24] Possible safety concerns include decreased absorption of carotenoids, fat-soluble vitamins, and antioxidants with consumption of high-dose phytosterols in humans.[25] Although several studies have suggested that circulating plant sterols are a risk factor for atherosclerosis, a recent review and meta-analysis revealed no association between serum concentrations of plant sterols and risk of cardiovascular disease.[25,26]

The lifestyle change program also played an integral role in our trial. It incorporated the Mediterranean diet,[27] an exercise program, and relaxation techniques, collectively shown to favorably affect serum lipids and reduce weight, blood pressure, and mortality.[28,29] Compared with the UCG, participants in the LCG had significant weight loss that was maintained throughout the 52-week trial. Total cholesterol and LDL-C were significantly lower in the LCG at weeks 12 and 24 compared with the UCG, but this difference was not significant at week 52.

Our study showed that RYR may be a safe and effective alternative therapy for treating low-risk hyperlipidemic patients with statin refusal or SAM. However, there are important limitations to its use. The composition of RYR was known and controlled in the current study (online Appendix Supplementary Table I), but there is limited regulation of RYR and variability of monacolins in different formulations.[30] Poorly manufactured products may contain citrinin, a mycotoxin.[30] Red yeast rice has been reported to cause myopathy,[31] rhabdomyolysis,[32] and hepatotoxicity and should be taken under the supervision of a physician. Because of these regulatory and quality issues, statins remain the medication of choice for treating hyperlipidemia, especially in intermediate-risk patients (Framingham risk score 10%-20%)[2] and high-risk patients with coronary risk equivalents or confirmed atherosclerotic disease. Clinicians should adhere to evidence-based guidelines and work with these patients, even those who are resistant to taking statins or those who are statin intolerant, to fine a statin drug that is well tolerated and effective.

Strengths of our study include the 2× 2 factorial design, multicenter enrollment, and its yearlong duration. Seventy-five percent of the enrolled subjects were women, reflecting the fact that women have a higher risk of SAM.[33] We achieved good compliance with our intervention in a study population often considered "noncompliant" by physicians because of statin intolerance or a refusal to take statins. There are several limitations. A large number of randomized participants (65/220) did not complete the trial (Figure 1). Half the dropouts (33/65) occurred after randomization but before initiation of the trial, whereas the other 32 participants dropped out after the trial began, most because of difficulty adhering to the study protocol. Participants in our study ingested 10 pills/d, which may limit compliance in a nonstudy population. The recidivism in the LCG at 52 weeks was concerning and highlights the difficulty of long-term adherence to a lifestyle change regimen. Our primary outcomes were limited to lipid measurements, and all analyses regarding the impact of RYR were limited to within-subject comparisons. Given our negative results, future studies need to evaluate if other phytosterol formulations or food products lower LDL-C in addition to RYR therapy in patients resistant to taking statins.

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