When Statins Hurt: Red Yeast Rice and LDL-cholesterol
When Statins Hurt: Red Yeast Rice and LDL-cholesterol
Abstract & Commentary
By Russell H. Greenfield, MD, Editor
Synopsis: In a well-designed RCT, researchers showed that a combination of healthy lifestyle training and the supplement red yeast rice successfully lowers LDL- cholesterol levels in people intolerant of prescription statin drugs due to myalgias, and without significant side effects. Variability in the quality of available red yeast rice supplements remains a significant concern.
Source: Becker DJ, et al. Red yeast rice for dyslipidemia in statin-intolerant patients: A randomized trial. Ann Intern Med 2009;150:830-839.
In a randomized, controlled intervention trial, researchers investigated the effectiveness and tolerability of red yeast rice in combination with training in therapeutic lifestyle change to treat elevated cholesterol levels in people with previous statin-associated myalgia (SAM). Subjects were recruited from a single cardiology practice in suburban Philadelphia and were 21-80 years of age with dyslipidemia and a history of discontinuation of statin therapy due to myalgias. A total of 174 subjects were screened and 112 were deemed ineligible or refused to participate, leaving 62 participants (40 women), with evaluable data available on 59 at trial's end (30 in the red yeast rice group). They were randomly assigned to receive either 1,800 mg (three 600 mg tablets) of red yeast rice twice daily or placebo twice daily for a total of 24 weeks. All subjects were also enrolled in a 12-week therapeutic lifestyle change program comprising a weekly 3.5 hour meeting where information was shared about cardiovascular disease, nutrition, exercise, and relaxation techniques. Participants were stratified into four categories: LDL-cholesterol < 3.9 mmol/L (150 mg/dL); LDL-cholesterol > 3.9 mmol/L (150 mg/dL); BMI < 27 kg/m2; and BMI > 27 kg/m2. Baseline laboratory tests and measurements were taken. All patients and study team members were blind to treatment allocation.
Subjects received a 30-day supply of tablets at monthly visits, at which time exercise and dietary logs were reviewed. At the end of the initial 12-week intervention period, lab tests and measurements were again taken. At that time, subjects were instructed to continue taking their pills and to follow the lifestyle instructions they had been given. Final fasting laboratory tests and measurements were performed at trial's end (week 24). Primary outcome was LDL-cholesterol, which was measured at baseline, 12 weeks (end of therapeutic lifestyle intervention), and at 24 weeks. Secondary outcomes included total cholesterol, HDL-cholesterol, triglycerides, liver function tests, creatinine kinase (CK), body weight, and results of the Brief Pain Inventory.
In the red yeast rice group at week 12, LDL-cholesterol had decreased by 1.11 mmol/L (43 mg/dL) from baseline. At week 24 a decrease of 0.90 mmol/L (35 mg/dL) was noted; in the placebo group, LDL-cholesterol decreased by 0.28 mmol/L (11 mg/dL) at week 12 and by 0.39 mmol/L (15 mg/dL) at week 24. LDL-cholesterol levels were significantly lower in the red yeast rice group than in the placebo group at both weeks 12 and 24, and significant treatment effects were observed on total cholesterol at both measurement times. The mean percentage change in LDL-cholesterol level from baseline for the red yeast rice group was -27.3% at week 12 and -21.3% at week 24; in the placebo group, mean percentage LDL-cholesterol change from baseline was -5.7% at 12 weeks and -8.7% at week 24. At week 24, nine of 30 subjects in the red yeast rice group achieved an LDL-cholesterol level of < 2.6 mmol/L (100 mg/dL) compared with two of 29 in the placebo group. No other significant changes were identified between measurements of the two groups.
Two of 29 in the red yeast rice group developed persistent intolerable myalgias and discontinued treatment, but their CK levels were within normal limits. One red yeast rice subject discontinued the agent due to dizziness, and one because of loose stools. One of the 30 members of the placebo group developed persistent intolerable myalgias and discontinued therapy but completed the study protocol. The groups did not differ with respect to development of myalgias or CK levels at week 12 or 24. The authors concluded that red yeast rice, when combined with therapeutic lifestyle change, may be a treatment option for dyslipidemic patients who cannot tolerate statins.
Commentary
This well-done study promotes a treatment for patients previously without a viable option, but the authors do not rest on the laurels of a positive study; instead they appropriately encourage further investigation to address lingering questions about red yeast rice, statin therapy, and dyslipidemia.
Statin therapy is generally well-tolerated, but a significant number of people (estimated by some to be up to 10% prescribed statin drugs, or up to 1.3 million people in the United States alone) develop SAM (which includes muscle weakness or fatigue), less frequently myositis (denoted by an elevation in CK), and rhabdomyolysis. Other known side effects include gastrointestinal upset and liver damage. While most people believe that side effects with statin therapy develops early on, SAM can occur up to 48 months after institution of therapy. Patients with SAM for whom treatment for elevated cholesterol levels is still indicated, and the practitioners caring for them, have previously been without good therapeutic choices.
Red yeast rice naturally contains monacolin K (or lovastatin) as well as other monacolins that inhibit HMG-CoA reductase. The incidence of recurrent SAM with a change in statin therapy is very high (estimated at 57%), yet therapy with red yeast rice appears to offer less risk for this side effect. The question is why, since both contain monacolins. While the answers currently promoted are not definitive, they make sense. First, it is known that SAM development is dose-dependent. The dosage of red yeast rice used in this study was 1,800 mg/d, high by usual standards, yet equivalent to only about 6 mg of lovastatin, far less than the typically prescribed dose of 20-40 mg/d. The low dosage may have been too low to elicit SAM, but there is no arguing the fact that treatment with red yeast rice was effective at lowering LDL-cholesterol. The researchers point out that perhaps there are other ingredients present within red yeast rice besides monacolins that play a therapeutic role and do not contribute to the incidence of SAM. In addition, the six-month trial duration may have been too short for SAM to show up.
Many practitioners rely on the concomitant use of coenzyme Q10 for their patients on statin therapy in the hope of forestalling SAM. Though some research results question this policy, experience has been good, for the most part. Noteworthy are the findings of recent studies that have implicated low vitamin D levels as contributing to development of mild-to-moderate SAM.1
Keep in mind that the study, while very good, had a small sample size and monitored adherence to study protocol by self-report. The trial was also of relatively short duration and was performed in a relatively affluent community, raising questions of generalizability. It is important not to lose sight of the contribution of healthy lifestyle training to the positive results (a decrease of LDL-cholesterol at trial's end of 8.7%). Interestingly, the improvement in the red yeast rice group lessened from 12 to 24 weeks (the authors believe this to be secondary to diminished protocol compliance).
Prevention through dietary and lifestyle measures remains the cornerstone of lipid-lowering therapy. Specifically with regard to red yeast rice, there is a paucity of data on long-term effects on cardiovascular disease risk reduction, if any, and incidence of SAM and other side effects. In addition, red yeast rice is a supplement available over the counter without a practitioner's involvement. Side effects such as SAM and liver dysfunction have been associated with red yeast rice use, and supplement quality can still vary between products to this day. Red yeast rice appears a reasonable choice for the treatment of hyperlipidemia in patients previously intolerant of statins due to SAM, but still should be instituted under a doctor's supervision.
Reference
1. Ahmed W, et al. Low serum 25 (OH) vitamin D levels (<32 ng/mL) are associated with reversible myositis-myalgia in statin-treated patients. Transl Res 2009:153:11-16.
In a well-designed RCT, researchers showed that a combination of healthy lifestyle training and the supplement red yeast rice successfully lowers LDL- cholesterol levels in people intolerant of prescription statin drugs due to myalgias, and without significant side effects.Subscribe Now for Access
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