David J. Becker

Red Yeast Rice for Dyslipidemia in Statin-Intolerant Patients: A Randomized Trial

Context Statin-associated myalgias prevent some patients who would benefit from drug therapy for dyslipidemia from receiving it. Red yeast rice is a dietary supplement that can decrease low-density lipoprotein (LDL) cholesterol level and could be a treatment option for patients with statin-associated myopathy. Contribution After 12 and 24 weeks, patients who received red yeast rice, 1800 mg twice daily, had significantly larger improvements in both LDL and total cholesterol levels than did patients who received placebo. Pain, creatinine phospho-kinase levels, and liver enzyme levels did not differ between groups. Implication Red yeast rice may be a treatment option for dyslipidemic patients who cannot tolerate statins. The Editors Statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors) are the most effective lipid-lowering medications for primary and secondary prevention of coronary artery disease (13). Although statins are generally well tolerated, some patients experience adverse effects, including elevated hepatic enzyme levels; gastrointestinal symptoms; and statin-associated myalgias (SAMs), which include muscle pain and weakness. Myositis (elevated creatinine phosphokinase [CPK] level) and rhabdomyolysis are more serious but rare complications of therapy (4). Statin-associated myalgias are dose related and typically occur in the absence of myositis. Currently, no optimal treatment exists for patients who develop SAM but still require therapy for hyperlipidemia. Because of SAM, patients may seek alternative therapies to manage their hypercholesterolemia, including red yeast rice (Monascus purpureus), a widely available dietary supplement that has been used as an herbal medication in China for centuries. Red yeast rice decreases low-density lipoprotein (LDL) cholesterol level (57), but no trials have investigated its use in patients with SAM. Our primary goal was to assess the efficacy and tolerability of red yeast rice for hypercholesterolemia in patients with previous SAM. We enrolled all patients in a therapeutic lifestyle change program and compared the lipid-lowering efficacy of red yeast rice with placebo in patients with a history of intolerance to at least 1 statin. Methods Design Overview We recruited patients from a cardiology practice in suburban Philadelphia. The institutional review board of Chestnut Hill Healthcare approved the trial, and all patients gave written informed consent. All authors had complete access to the primary data. Setting and Patients Patients were eligible if they were 21 to 80 years of age; had known hypercholesterolemia; and had discontinued at least 1 statin because of myalgias, with resolution of muscle pain when the medication was discontinued. We excluded patients if they had received a statin or red yeast rice in the month before random assignment; had a history of statin-associated myositis, rhabdomyolysis, chronic pain, or inability to exercise; had myocardial infarction, percutaneous coronary intervention, or coronary artery bypass grafting in the previous 6 months; had received weight-loss medications or dietary supplements that might mitigate SAM or decrease lipid levels; or had abnormal baseline laboratory values (LDL cholesterol level <2.6 mmol/L [<100 mg/dL] or >5.5 mmol/L [>210 mg/dL], triglyceride level 4.4 mmol/L [400 mg/dL], CPK level >500 U/L, aspartate transferase or alanine transferase level >1.5 times the upper limit of normal, or an abnormal thyroid-stimulating hormone level). Randomization and Interventions Figure 1 shows the flow of patients through the trial. We recruited patients between September 2006 and March 2007. We screened 174 patients with SAM; 112 were ineligible for the study or declined to participate. Sixty-two patients were randomly assigned, and baseline laboratory tests were drawn and measurements taken. Table 1 shows baseline characteristics. Figure 1. Study flow diagram. LDL = low-density lipoprotein; TLC = therapeutic lifestyle change; TSH = thyroid-stimulating hormone. Table 1. Baseline Patient Characteristics We randomly assigned all enrolled patients to receive three 600-mg capsules of red yeast rice (1.8g by weight) or 3 placebo capsules twice daily for 24 weeks. We randomly assigned patients in blocks of 4 and stratified them into 4 categories to improve power and subgroup analyses: LDL cholesterol level less than 3.9 mmol/L (<150 mg/dL), LDL cholesterol level of 3.9 mmol/L or greater (150 mg/dL), body mass index less than 27 kg/m2, and body mass index of 27 kg/m2 or greater. We generated the random assignment list on a computer by using the blockrand library (8) of the R programming environment with the fixed-block option (9). We purchased both the red yeast rice and placebo directly from the manufacturer (Sylvan Bioproducts, Kittanning, Pennsylvania); they were identical in size, shape, and color. Participants received a 30-day supply of study product at monthly visits. At the end of the trial, we assessed treatment adherence by self-report of the average number of missed doses per week. All patients also enrolled in our previously published, multidisciplinary, 12-week therapeutic lifestyle change program (10). Briefly, patients attended weekly 3.5-hour meetings and were taught about cardiovascular disease, nutrition, exercise, and relaxation techniques (Appendix). After the therapeutic lifestyle change program ended at week 12, we again conducted laboratory tests and took measurements. We then instructed patients to follow the recommendations of the program and continue to take their study medication for an additional 12 weeks. We held meetings each month to review dietary and exercise logs and provide study product. Attendance in the 12-week program and all subsequent monthly meetings was 92%. All patients and study team members were blinded to treatment allocation throughout the 24-week study. At week 24, we conducted the final laboratory tests and took the final measurements. One patient in the red yeast rice group dropped out at week 10 because he could not attend the program. Two patients in the placebo group dropped out, 1 at week 12 because of newly diagnosed hypothyroidism and 1 at week 16 because of nonadherence to the lifestyle change program. Fifty-nine patients completed the 24-week study: 30 in the red yeast rice group and 29 in the placebo group. We conducted the study between April 2007 and October 2007. Outcomes and Follow-up The primary outcome was LDL cholesterol level, measured at baseline, week 12 (end of the therapeutic lifestyle change program), and week 24 (end of the study). Other secondary outcomes included total cholesterol level, high-density lipoprotein cholesterol level, triglyceride level, and weight. Safety All patients completed the Brief Pain Inventory Short Form (BPI-sf) (Appendix Figure) at baseline, week 12, and week 24. The BPI-sf is a validated, widely used, self-administered questionnaire developed to assess the severity of pain and the effect of pain on daily function (11). To assess pain severity, we used a question from the Brief Pain Inventory Pain Severity subscale that asks about average pain severity over the past week (on a 0- to 10-point scale) rather than calculate a mean score across all items. We used this for the secondary outcome of measuring pain severity score at baseline, week 12, and week 24. We also assessed safety by measuring CPK and liver-associated enzyme levels in all patients at baseline, week 12, and week 24. We reviewed the results of laboratory tests independently at week 12 to monitor safety. Appendix Figure. Brief Pain Inventory Short Form questionnaire. Reproduced with permission of Charles Cleeland, PhD (ccleeland@mail.mdanderson.org). Anthropometry We measured weight to the nearest 0.1kg and height to the nearest centimeter at baseline, week 12, and week 24. We calculated body mass index as weight (kg) divided by height (m)2. We measured blood pressure in patients in the sitting position by using standard sphygmomanometry. Laboratory We obtained a fasting blood sample at baseline, week 12, and week 24 for a lipid panel, complete metabolic profile, and CPK and thyroid-stimulating hormone levels. The Laboratory Corporation of America (Burlington, North Carolina) performed the analyses. ConsumerLab.com (White Plains, New York) analyzed the red yeast rice (Table 2). The laboratory tested red yeast rice for individual and total monacolins by using high-performance liquid chromatography. They used thin-layer chromatography to detect citrinin, a potential contaminant. We did not disclose the identity of the products to the laboratory performing the testing. Table 2. Chemical Analysis Statistical Analysis We used the intention-to-treat principle for all data analysis on the patients at baseline and week 12. We computed descriptive statistics for primary and secondary outcome measures at baseline, week 12, and week 24. We assumed outcomes were normally distributed and fit a linear mixed-effects model for each outcome to account for the correlation due to repeated measurements. Each model allowed for patient-specific intercepts. We modeled raw outcomes together (baseline, week 12, and week 24), and the model included an interaction term between treatment indicator and the 3-level categorical variable for week. These models gave an estimate of the treatment effect, which represents the estimated difference in the mean outcome between the red yeast rice and placebo groups at weeks 12 and 24. Specifically, these models provided point estimates and CIs for differences in the mean LDL cholesterol, total cholesterol, high-density lipoprotein cholesterol, and triglyceride levels; BPI-sf pain scores; and body mass index between the treatment and placebo groups at weeks 12 and 24. We also used each model to test for a difference between the treatment effect at weeks 12 and 24 to evaluate any change in the treatment effect over this time. The m

Tolerability of Red Yeast Rice (2,400 mg Twice Daily) Versus Pravastatin (20 mg Twice Daily) in Patients With Previous Statin Intolerance

Currently, no consensus has been reached regarding the management of hyperlipidemia in patients who develop statin-associated myalgia (SAM). Many statin-intolerant patients use alternative lipid-lowering therapies, including red yeast rice. The present trial evaluated the tolerability of red yeast rice versus pravastatin in patients unable to tolerate other statins because of myalgia. The study was conducted in a community-based setting in Philadelphia, Pennsylvania. A total of 43 adults with dyslipidemia and a history of statin discontinuation because of myalgia were randomly assigned to red yeast rice 2,400 mg twice daily or pravastatin 20 mg twice daily for 12 weeks. All subjects were concomitantly enrolled in a 12-week therapeutic lifestyle change program. The primary outcomes included the incidence of treatment discontinuation because of myalgia and a daily pain severity score. The secondary outcomes were muscle strength and plasma lipids. The incidence of withdrawal from medication owing to myalgia was 5% (1 of 21) in the red yeast rice group and 9% (2 of 22) in the pravastatin group (p = 0.99). The mean pain severity did not differ significantly between the 2 groups. No difference was found in muscle strength between the 2 groups at week 4 (p = 0.61), week 8 (p = 0.81), or week 12 (p = 0.82). The low-density lipoprotein cholesterol level decreased 30% in the red yeast rice group and 27% in the pravastatin group. In conclusion, red yeast rice was tolerated as well as pravastatin and achieved a comparable reduction of low-density lipoprotein cholesterol in a population previously intolerant to statins.

Simvastatin vs Therapeutic Lifestyle Changes and Supplements: Randomized Primary Prevention Trial

OBJECTIVE To compare the lipid-lowering effects of an alternative regimen (lifestyle changes, red yeast rice, and fish oil) with a standard dose of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin). PATIENTS AND METHODS This randomized trial enrolled 74 patients with hypercholesterolemia who met Adult Treatment Panel III criteria for primary prevention using statin therapy. All participants were randomized to an alternative treatment group (AG) or to receive simvastatin (40 mg/d) in this open-label trial conducted between April 1, 2006, and June 30, 2006. The alternative treatment included therapeutic lifestyle changes, ingestion of red yeast rice, and fish oil supplements for 12 weeks. The simvastatin group received medication and traditional counseling. The primary outcome measure was the percentage change in low-density lipoprotein cholesterol (LDL-C). Secondary measures were changes in other lipoproteins and weight loss. RESULTS There was a statistically significant reduction in LDL-C levels in both the AG (-42.4%+/-15%) (P<.001) and the simvastatin group (-39.6%+/-20%) (P<.001). No significant differences were noted between groups. The AG also demonstrated significant reductions in triglycerides (-29% vs -9.3%; 95% confidence interval, -61 to -11.7; P=.003) and weight (-5.5% vs -0.4%; 95% confidence interval, -5.5 to -3.4; P<.001) compared with the simvastatin group. CONCLUSION Lifestyle changes combined with ingestion of red yeast rice and fish oil reduced LDL-C in proportions similar to standard therapy with simvastatin. Pending confirmation in larger trials, this multifactorial, alternative approach to lipid lowering has promise for a subset of patients unwilling or unable to take statins.

Phytosterols, red yeast rice, and lifestyle changes instead of statins: a randomized, double-blinded, placebo-controlled trial.

BACKGROUND Many patients who refuse or cannot tolerate statin drugs choose alternative therapies for lipid lowering. OBJECTIVES This study aimed to determine the lipid-lowering effects of phytosterol tablets and lifestyle change (LC) on top of red yeast rice (RYR) therapy in patients with a history of statin refusal or statin-associated myalgias. DESIGN A total of 187 participants (mean low-density lipoprotein cholesterol [LDL-C], 154 mg/dL) took RYR 1800 mg twice daily and were randomized to phytosterol tablets 900 mg twice daily or placebo. Participants were also randomized to a 12-week LC program or usual care (UC). Primary end point was change in LDL-C at 12, 24, and 52 weeks. Secondary end points were effect on other lipoproteins, high-sensitivity C-reactive protein, weight, and development of myalgia. RESULTS Phytosterols did not significantly improve LDL-C at weeks 12 (P = .54), 24 (P = .67), or 52 (P = .76) compared with placebo. Compared with the UC group, the LC group had greater reductions in LDL-C at weeks 12 (-51 vs -42 mg/dL, P = .006) and 24 (-48 vs -40 mg/dL, P = .034) and was 2.3 times more likely to achieve an LDL-C <100 mg/dL (P = .004). The LC group lost more weight for 1 year (-2.3 vs -0.3 kg, P < .001). All participants took RYR and had significant decreases in LDL-C, total cholesterol, triglycerides, high-sensitivity C-reactive protein, and an increase in high-density lipoprotein cholesterol for 1 year when compared with baseline (P < .001). Four participants stopped supplements because of myalgia. CONCLUSIONS The addition of phytosterol tablets to RYR did not result in further lowering of LDL-C levels. Participants in an LC program lost significantly more weight and were more likely to achieve an LDL-C <100 mg/dL compared with UC.

Red Yeast Rice for Dyslipidemia in Statin-Intolerant Patients

Red yeast rice is a dietary supplement that can decrease low-density lipoprotein (LDL) cholesterol levels and could be a treatment option for patients with statin-associated myopathy. Investigators...

The lipid-lowering properties of red yeast rice.

Red yeast rice is an over-the-counter supplement, long used in China, that has shown lipid-lowering effects in trials. It has become popular among Americans but, until regulation and standardization improve, its use will remain controversial.