COMMENTARY

Red Yeast Rice and Hyperlipidemia: How Strong Is the Evidence?

Charles P. Vega, MD

Disclosures

October 28, 2009

Best Evidence Reference

Becker DJ, Godon RY, Halbert SC, French B, Morris PB, Rader DJ. Red yeast rice for dyslipidemia in statin-intolerant patients: a randomized trial. Ann Intern Med. 2009;150:830-839, W147-149.

This study was selected from Medscape Best Evidence, which uses the McMaster Online Rating of Evidence System. Of a possible top score of 7, this study was ranked as 5 for newsworthiness and 6 for relevance by clinicians who used this system.

Introduction

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, or statins, have proven to be effective in reducing lipid levels and improving the risk for cardiovascular disease. However, many patients may not tolerate statins over time, partly due to statin-associated myopathy. Does red yeast rice present a valid alternative treatment for patients with this adverse event? The randomized trial discussed in this review examined the efficacy, safety, and tolerability of red yeast rice among a cohort of patients with a history of statin-associated myopathy.

The significant benefits of statins are hard to refute. These are being reported even among patients at a low risk for cardiovascular disease. For example, in a 2009 study, within 12 months of the initiation of treatment, rosuvastatin was associated with significant regression of carotid intima-media thickness -- a strong surrogate marker for cardiovascular events.[1] Moreover, statin treatment among low-risk patients is associated with a reduction in the risk for cardiovascular events. The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) examined treatment with lovastatin vs placebo among patients without a history of cardiovascular events.[2] Researchers found that lovastatin reduced the risk for first coronary heart disease events by nearly half over an average follow-up time of 5.2 years. This included a 40% reduction in the risk for myocardial infarction. There was also no significant difference in the rate of severe adverse events when comparing the lovastatin and placebo groups.

Statin-Associated Myopathy and Rhabdomyolysis

Regardless of their benefits, statins are not completely benign medications. Rhabdomyolysis, a life-threatening condition, is associated with statin use. It remains very rare, with a rate of approximately 3.4 cases per 100,000 person-years of statin use.[3] Of note, the risk for rhabdomyolysis is increased approximately 10 times among patients who have used a statin along with gemfibrozil. Fluvastatin and pravastatin may promote lower rates of rhabdomyolysis compared with other statins. There are wide-ranging estimates with regard to the prevalence of myopathy, defined by diffuse muscle pain and weakness, related to the use of statins. A review of statin safety reported an incidence of 11 cases per 100,000 person-years of use.[3] However, a retrospective review of billing data from one US hospital found that the prevalence of statin-induced myopathy was 10.3%.[4] These cases were not temporally related to the initiation of statin treatment; the mean duration of statin therapy prior to symptom onset was 6.3 months. Of note, 13% of patients in this series were hospitalized for rhabdomyolysis. The difference in the prevalence of myopathy when comparing the larger report of statin safety with the retrospective review from one hospital may be explained by the fact that the latter included patients taking cerivastatin, which was removed from the market in 2001 after it was associated with a higher rate of adverse events compared with other statins.

Adverse events can have a profound effect on adherence to therapy, and some evidence suggests that adherence is a major issue for chronic lipid-lowering therapy. In a study of patients for whom the cost of medications was not a profound issue influencing adherence, 40% of prescriptions for lipid-lowering therapy went unfilled.[5] Only half of the patients in the study continued lipid-lowering therapy for 5 years. The appropriate management of statin-associated myopathy may improve treatment adherence, but little consensus exists on the best way to do this. Each case requires an individualized approach with attention to patients' treatment goals for cardiovascular disease risk reduction. Either stopping the statin or lowering its dose may be a good option for some patients. A trial with a different statin was successful in resolving myopathy among 43% of patients in the series described above.[4] Ezetimibe could be helpful among patients with a lower target level of low-density lipoprotein (LDL) cholesterol.

Coenzyme Q10. There has been interest in the use of supplementation with coenzyme Q10 (CoQ10), to prevent or treat statin-associated myopathy. Statins may help reduce the production of CoQ10, which is concentrated in the mitochondria and helps reduce oxidative stress. However, there is little evidence to indicate that this intervention is effective. A small randomized, placebo-controlled trial of CoQ10 failed to demonstrate an improvement in myalgia symptoms or tolerability of simvastatin, although plasma CoQ10 levels increased with active treatment.[6]

Red Yeast Rice for Managing Statin-Associated Myopathy

One strategy in the management of patients with statin-associated myopathy could involve the use of red yeast rice, the fermented product of the yeast species Monascus purpureus grown on rice. It has been used for medicinal and nonmedicinal purposes in China since 900 A.D., and it is promoted there as a means to improve circulation. Red yeast rice contains several compounds collectively known as monacolins, one of which is monacolin K, a powerful HMG-CoA reductase inhibitor and the same chemical as lovastatin. Because of this, red yeast rice has received increased attention in Western countries as a means to treat hyperlipidemia, and there is good research to support its efficacy. In one placebo-controlled trial of 83 individuals with hyperlipidemia, red yeast rice was associated with mean reductions in the concentrations of total and LDL cholesterol of 18% and 22%, respectively, over 12 weeks of treatment.[7] Red yeast rice also reduced serum triglyceride levels by 7% but did not significantly alter high-density lipoprotein (HDL) cholesterol levels. In another placebo-controlled trial, red yeast rice reduced total and LDL cholesterol levels by 27.7% and 21.5%, respectively, and red yeast rice decreased apolipoprotein B levels by 26%.[8]

To help determine whether red yeast rice may be useful among patients with hyperlipidemia who do not tolerate a statin, the study under discussion in this review compared red yeast rice and placebo among patients with statin-associated myopathy. Patients from one cardiology practice in the United States were eligible for study participation if they were between 21 and 80 years old and had discontinued a statin because of myalgia. Participants' LDL cholesterol levels were between 100 and 210 mg/dL at baseline, and patients with a serum triglyceride level of 400 mg/dL or more were excluded from study participation, as were those with a history of coronary heart disease.

Sixty-two patients underwent randomization to treatment with 3 red yeast rice 600-mg capsules twice daily, or matching placebo capsules with the same dosing schedule. The treatment period was 24 weeks. All study participants had previously been enrolled in a 12-week trial of lifestyle counseling to prevent cardiovascular disease. The mean age of the participants was 61 years, and 65% of the participants were women. The mean patient weight at baseline was 81 kg. The 2 groups were similar at baseline, except for a slightly higher mean pain score in the placebo cohort.

The main study outcome was LDL cholesterol level, as measured at baseline, week 12, and week 24. The mean values in the placebo group were 165 mg/dL, 154 mg/dL, and 149.8 mg/dL at baseline, week 12, and week 24. The respective levels of LDL cholesterol in the red yeast rice group were significantly better during the active trial period (163 mg/dL, 120 mg/dL, and 128 mg/dL, respectively). This represented a decrease in the baseline LDL cholesterol level of -27.3% at 12 weeks and -21.3% at 24 weeks in the red yeast rice group. Total cholesterol levels were also improved in the red yeast rice vs placebo groups, but there was no treatment difference in HDL cholesterol or triglyceride levels.

Researchers also examined other lipid values and patient weight, as well as specific surveys for bodily pain and laboratory assessments of creatine phosphokinase levels and liver-associated enzymes. There was no significant difference between the red yeast rice and placebo groups in the rate of adverse events and bodily pain, even when the researchers performed a subgroup analysis that was based on the number of statins that patients had previously tried. Four patients discontinued treatment in the red yeast rice group, compared with 1 patient in the placebo group. Creatine phosphokinase and liver-associated enzyme levels remained similar between the groups. Both treatment groups experienced a weight loss of approximately 3.5 kg from baseline.

Commentary

The collective research suggests that red yeast rice is effective and safe in improving the lipid profile among patients with hyperlipidemia. Some research even has suggested that red yeast rice, along with other nonprescription treatment, may be as or more effective than a statin. Becker and colleagues compared treatment with simvastatin 40 mg daily vs combination therapy consisting of enrollment in an intensive lifestyle intervention, fish oil supplementation, and red yeast rice supplementation.[9] The reduction in LDL cholesterol was approximately 40% in both treatment groups, and patients receiving the combination treatment experienced a greater reduction in body weight and serum triglycerides. Although these results are impressive, it is unclear which of the nonstatin interventions was most effective in improving study outcomes.

Red yeast rice does not have the impressive track record of statins in terms of the prevention of cardiovascular events. However, a trial of 5000 individuals with a history of previous myocardial infarction demonstrated that red yeast rice reduced the risk for nonfatal myocardial infarction by 62% and coronary disease mortality by 31% compared with placebo.[10] Red yeast rice also reduced overall mortality by one third compared with placebo.

More research is required with regard to the clinical outcomes of red yeast rice before this treatment can be recommended as an alternative to statins to treatment-naive patients with hyperlipidemia. Concerns about red yeast rice toxicity have been based on monacolin K, the natural lovastatin. Myopathy and rhabdomyolysis,[11,12] similar to that seen with lovastatin, have been reported in case reports. Hepatotoxicity is the main concern, with reports on red yeast rice's effects on the liver being variable. Some studies have shown theoretical potential for hepatic damage,[13,14] and others have reported no harm in humans.[15] In some animal studies (rats and mice), high doses were tolerated without liver toxicity.[16,17,18] Because of this finding, statins themselves and any agents that interact with statins should be avoided by those taking red yeast rice.

There are also common questions associated with any complementary and alternative therapy about standardization of the preparation and reimbursement for long-term treatment. However, among special cohorts of patients, particularly those with statin-associated myopathy, red yeast rice appears to be a viable alternative treatment. Physicians should weigh the potential risks and benefits of statins vs alternative treatments for individual patients on the basis of their history of treatment and cardiovascular risk.

Clinical Pearls

  • Treatment with statins is associated with a reduction in cardiovascular risk, even among low-risk patients;

  • There are variable estimates with regard to the prevalence of myopathy among statin users, and there is no consensus about the best means to treat statin-associated myopathy;

  • Previous research found that red yeast rice is significantly superior to placebo in the treatment of hyperlipidemia; and

  • In the current study focused on patients with a history of statin-induced myopathy, red yeast rice was effective in reducing total and LDL cholesterol values effectively and safely.

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