Red Yeast Rice Preparations: Are They Suitable Substitutions for Statins?

Red yeast rice, a commercially available food supplement known to reduce serum cholesterol, has been repeatedly advocated as alternative therapy for hypercholesterolemic patients that refuse statins, cannot tolerate statin therapy's side effects, or request a "naturopathic" medicine. Red yeast rice contains a fungus (Monascus purpureus), which was utilized in the original production of lovastatin (MEVACOR, Merck & Co, Whitehouse Station, NJ), the first marketed pharmaceutical statin, and is chemically identical to such product. Their identical properties account for the similarity in therapeutic and side effects of red yeast rice and lovastatin. The red yeast rice ingredient that blocks cholesterol production is monacolin K. Because red yeast rice preparations have large variability in monacolin K content, predicting or understanding dose-related efficacy and side-effect risks of red yeast rice is practically impossible. The lipid-regulating potency of red yeast rice in commercial preparations was found to be extensively different according to the number or concentration of monacolin K they possess. Furthermore, more than one type of monacolin was found in different preparations (or batches) of red yeast rice. Other ingredients found in red yeast rice are also known to be potentially toxic. The US Food and Drug Administration issued warnings to consumers in 2007 and in 2013 against taking red yeast rice products due to the lack of assurance about its efficacy, safety, and lack of standardized preparation methods. This article discusses my clinical trial results with red yeast rice, reviews the literature on its therapeutic and side effects, and discusses why red yeast rice is not an acceptable substitution for statins.

A systematic review on evidence of the effectiveness and safety of a wax-matrix niacin formulation.

Niacin is a uniquely efficacious therapy in the treatment of dyslipidemia because of its broad spectrum of beneficial effects on every aspect of the lipid profile and because it has been shown to reduce both total mortality and coronary death. However, niacin therapy is hindered by its side-effect profile, which appears to be dependent on its formulation with immediate-release niacin, associated with a greater incidence of flushing, and sustained-release niacin, associated with greater liver function test (LFT) abnormalities and hepatotoxicity. One such sustained-release niacin nutritional supplement formulation, Endur-acin (Endurance Products Company, Tigard, OR), claims to have clinical evidence to support its use in the treatment of dyslipidemias, which prompted us to systematically review the literature. We identified four published papers in which the authors reported the results of two separate clinical trials and one pharmacokinetic study that fulfilled the inclusion criteria and were included in this review. Endur-acin significantly reduced total cholesterol, low-density lipoprotein cholesterol, and total cholesterol/high-density lipoprotein cholesterol ratio with mean reductions up to 19%, 26%, and 20%, respectively, at a dose of 2000 mg/day. Less-impressive benefits were also seen with high-density lipoprotein cholesterol (+10%) and serum triglycerides (-23%). Mean LFT elevations of up to 1.6-fold were seen at the 2000 mg per day dose, however, not exceeding three times the upper limit of normal, with abnormal results occurring at similar frequency in placebo and one patient experiencing marked gastrointestinal symptoms and a hepatitis-like syndrome with reversible elevated LFT. Short-term randomized controlled trials suggest Endur-acin is effective in modifying serum lipids, although study limitations prevent a comprehensive evaluation of safety.

What combination therapy with a statin, if any, would you recommend?

The latest recommended goals for blood lipid levels may require multiple lipid drugs. Lower doses in combination may render more efficacy and safety than highest doses of single agents. Except for isolated hypoalphalipoproteinemia (a low level of high-density lipoprotein cholesterol), therapies will start with a statin. All marketed statins are acceptable. The choice may be based on dose- efficacy and patient's tolerability. High-potency statins (eg, atorvastatin, simvastatin, or rosuvastatin) are often chosen. Currently, generic statins, such as simvastatin, lovastatin, pravastatin, and fluvastatin, offer cost benefits. The choice of added agent depends on the "residual lipoprotein abnormalities" after statin therapy, efficacy, compliance issues, and cost. Approved "combined" preparations improve cost and compliance. To further lower low-density lipoprotein cholesterol, ezetimibe is a safe, efficacious choice, pending resolution of a controversial trial's results. Colesevelam is moderately effective and the best tolerated bile acids sequestrant. In combined dyslipidemias, extended-release niacin is the best tolerated niacin preparation; other quality-controlled immediate-release preparations have similar safety and efficacy but produce more flushing of the skin. Niacin or fenofibrate is effective in normalizing high-density lipoprotein and triglyceride levels persisting after statin therapy. Agents approved by the US Food and Drug Administration and the latest guidelines of the National Cholesterol Education Program, American Heart Association/American College of Cardiology provide choices and indications of drug combinations.

Pleiotropic effects: should statins be considered an essential component in the treatment of dyslipidemia?

Cardiovascular disease (CVD) is the leading cause of death in the developed world. Lower risks of morbidity and mortality in trials of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) have changed the conventional wisdom regarding lipid lowering. Since 2001, there have been surprising results concerning the early benefits of statin therapy, which suggest that some benefits may be derived from effects other than those of simply improving dyslipidemias. The earlier than expected CVD benefits from statin trials have led to the theory that statins have effects other than, or concomitant to, the benefits on serum lipid levels, and that these effects may be at least partly responsible for their early and often significant reduction in CVD risk. These have been defined as pleiotropic effects. Possible means by which statins reduce CVD risk independent of their lipid regulation may include antithrombotic and anti-inflammatory effects, antioxidation, plaque stabilization, and endothelial wall relaxation resulting in lower intra-arterial pressure and increased blood flow.

Adiposopathy is a more rational treatment target for metabolic disease than obesity alone.

Current guidelines recommend that weight-loss therapy should be primarily based upon specific body mass index (BMI) cut-off limits. However, in the adipocentric paradigm, it is acknowledged that co-morbidities, such as type 2 diabetes mellitus, hypertension, and dyslipidemia, occur at all levels of BMI. Excessive fat mass (adiposity) in genetically susceptible individuals results in fat dysfunction (adiposopathy), which then contributes to metabolic disorders that increase the risk of atherosclerotic cardiovascular disease. In this paradigm, the term "anti-obesity" treatment might best be replaced by "anti-adiposopathy" treatment, wherein the focus is not based solely on BMI, but instead directed towards physiologically improving fat cell function and clinically improving the metabolic health of patients. This may occur through appropriate diet, physical exercise, and other lifestyle changes, and/or from drug therapies. Cannabinoid receptor antagonists and peroxisome proliferator activated receptor agonists are examples of agents that physiologically improve fat function and clinically improve metabolic disease.

Treatment of Familial Hypercholesterolemia and Other Genetic Dyslipidemias.

Despite their inherited nature, familial dyslipidemias show large intra- and interfamilial variability in phenotypic expression, clinical presentations, and levels of abnormalities of serum lipid fractions. Once diagnosed, patients shall be considered at high cardiovascular risk and treated as per secondary prevention National Cholesterol Education Program III guidelines. Comorbidity treatments (ie, obesity, diabetes, and hypertension) are imperative. Lifestyle interventions shall soon be concomitantly followed by lipid-regulating drugs. The major aspects of the above interventions are the following: 1) therapeutic lifestyle change: regular aerobic exercises, conventional low-fat, low-cholesterol, low refined but high complex carbohydrates diet, avoidance of unproven fad diets (ie, Atkins); 2) plant stanols and sterol esters, 3) high-potency statins (eg, rosuvastatin, simvastatin, atorvastatin); 4) addition of nicotinic acid, bile acid binders, fibrates, or ezetimibe pending on the lipid fraction affected; 5) statins are the starting drug of choice with these exceptions: in isolated low-density lipoprotein cholesterol, niacin or fibrates may be preferable; in isolated severe hypertriglyceridemic conditions, fibrates or fish oil may be preferable; in children with isolated elevation of low-density lipoprotein cholesterol, ezetimibe or bile acid binders may be preferable; when serum lipoprotein (a) elevation is the most notable abnormality, niacin may be chosen as the initial drug for its unique effect on this fraction. Plasmapheresis, intestinal shunts, or liver transplantation are to be considered in that order as last resorts if the above fails to accomplish serum lipid level goals.

Differential effects of simvastatin and atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I are consistent across hypercholesterolemic patient subgroups.

BACKGROUND: In addition to lowering plasma levels of low-density lipoprotein cholesterol (LDL-C), statins also raise high-density lipoprotein cholesterol (HDL-C). HYPOTHESIS: Recent studies have shown that treatment with simvastatin results in larger increases in HDL-C than those seen with atorvastatin. The results of three clinical studies are analyzed, comparing the effects of simvastatin and atorvastatin on HDL-C and apolipoprotein A-I (apo A-I) in the total cohort and in several subgroups of hypercholesterolemic patients. The three studies were all multicenter, randomized clinical trials that included simvastatin (20-80 mg) and atorvastatin (10-80 mg) treatment arms. The subgroup analyses performed were gender; age (< 65 and > or = 65 years); baseline HDL-C (male: < 40 or > or = 40 mg/dl; female: < 45 or > or = 45 mg/dl), baseline LDL-C (< 160 or > or = 160 mg/dl), and baseline triglycerides (< 200 or > or = 200 mg/dl). RESULTS: Both drugs produced similar increases in HDL-C levels at low doses; however, at higher drug doses (40 and 80 mg), HDL-C showed a significantly greater increase with simvastatin than with atorvastatin (p < 0.05 to < 0.001). Therefore, while HDL-C remained consistently elevated across all doses of simvastatin, there appeared to be a pattern of decreasing HDL-C with an increasing dose of atorvastatin. A similar negative dose response pattern was also observed with apo A-I in atorvastatin-treated patients, suggesting a reduction in the number of circulating HDL particles at higher doses. Both drugs reduced LDL-C and triglycerides in a dose-dependent fashion, with atorvastatin showing slightly greater effects. The differential effects of atorvastatin and simvastatin on HDL-C and apo A-I were observed for both the whole study cohorts and all subgroups examined; thus, no consistent treatment-by-subgroup interactions were observed. CONCLUSION: The data presented show that, across different hypercholesterolemic patient subgroups, simvastatin increases HDL-C and apo A-I more than atorvastatin at higher doses, with evidence of a negative dose response effect on HDL-C and apo A-I with atorvastatin, but not simvastatin.

Effectiveness and tolerability of a new lipid-altering agent, gemcabene, in patients with low levels of high-density lipoprotein cholesterol.

This study evaluated the efficacy and tolerability of gemcabene, a new lipid-altering agent, in a double-blind, randomized, dose-response study of 161 patients with high-density lipoprotein (HDL) cholesterol of <35 mg/dl and serum triglyceride (TG) levels of either >/=200 (n = 94) or <200 mg/dl (n = 67). After a 6-week, placebo, dietary lead-in period, patients were administered either 150, 300, 600, or 900 mg of gemcabene or placebo once daily for 12 weeks. In the TG >/=200 mg/dl stratum, gemcabene significantly increased serum HDL cholesterol by 18% with corresponding significant increases of 6% in both apolipoprotein A-I and A-II levels at the 150-mg dose. HDL cholesterol levels also increased 12% at the 300-mg dose; however, this did not reach statistical significance. Also, in the TG >/=200 mg/dl stratum, serum TG levels were significantly reduced by 27% and 39% at the 150- and 300-mg doses of gemcabene, respectively. No significant differences were found in serum HDL cholesterol or TG levels in the TG >/=200 mg/dl groups that received 600 or 900 mg of gemcabene, or in TG <200 mg/dl groups administered any dose of gemcabene. However, at these higher 600- and 900-mg doses, gemcabene significantly reduced serum low-density lipoprotein (LDL) cholesterol levels by 15% to 25%, respectively, in both TG strata, with proportionate decreases in the levels of apolipoprotein B. Gemcabene was well tolerated with a frequency of adverse events similar to that of placebo. In conclusion, at the lower doses, gemcabene significantly increased HDL cholesterol and reduced TG serum levels in patients with low HDL cholesterol and TG >/=200 mg/dl. At the higher doses, gemcabene significantly reduced LDL cholesterol levels in all patients with low HDL cholesterol.

Comparison of once-daily, niacin extended-release/lovastatin with standard doses of atorvastatin and simvastatin (the ADvicor Versus Other Cholesterol-Modulating Agents Trial Evaluation [ADVOCATE]).

This study compared the relative efficacy of a once-daily niacin extended-release (ER)/lovastatin fixed-dose combination with standard doses of atorvastatin or simvastatin, with a special emphasis on relative starting doses. Subjects (n = 315) with elevated low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cholesterol blood levels (defined as LDL cholesterol blood levels > or =160 mg/dl without coronary artery disease, or > or =130 mg/dl if coronary artery disease was present, and HDL cholesterol <45 mg/dl in men and <50 mg/dl in women) were randomized to atorvastatin, simvastatin, or niacin ER/lovastatin for 16 weeks. The primary efficacy variables were the mean percent change in LDL cholesterol and HDL cholesterol levels from baseline. After 8 weeks, the starting dose niacin ER/lovastatin 1,000/40 mg and the 10-mg starting dose atorvastatin both lowered mean LDL cholesterol by 38%. After 12 weeks, niacin ER/lovastatin 1,000/40 mg lowered LDL cholesterol by 42% versus 34% with the 20-mg starting dose of simvastatin (p <0.001). Niacin ER/lovastatin increased HDL cholesterol significantly more than atorvastatin or simvastatin at all compared doses (p <0.001). Niacin ER/lovastatin also provided significant improvements in triglycerides, lipoprotein(a), apolipoprotein A-1, apolipoprotein B, and HDL subfractions. A total of 6% of study subjects receiving niacin ER/lovastatin withdrew because of flushing. No significant differences were seen among study groups in discontinuance due to elevated liver enzymes. No drug-induced myopathy was observed. Niacin ER/lovastatin was comparable to atorvastatin 10 mg and more effective than simvastatin 20 mg in reducing LDL cholesterol, was more effective in increasing HDL cholesterol than either atorvastatin or simvastatin, and provided greater global improvements in non-HDL cholesterol, triglycerides, and lipoprotein(a).

Effects of simvastatin, an HMG-CoA reductase inhibitor, in patients with hypertriglyceridemia.

BACKGROUND: Patients with elevated levels of serum triglycerides (TG) often have other associated lipid abnormalities (e.g., low levels of high-density lipoprotein cholesterol [HDL-C]) and are at increased risk of developing coronary heart disease. Although the therapeutic benefits of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in hypercholesterolemic patients have been well established, less is known about the effects of statins in patient populations with hypertriglyceridemia. HYPOTHESIS: The purpose of this study was to evaluate the lipoprotein-altering efficacy of simvastatin in hypertriglyceridemic patients. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study. In all, 195 patients with fasting serum triglyceride levels between 300 and 900 mg/dl received once daily doses of placebo or simvastatin 20, 40, or 80 mg for 6 weeks. RESULTS: Compared with placebo, simvastatin treatment across all doses resulted in significant reductions (p < 0.05 - < 0.001) in serum levels of triglycerides (-20 to -31% decrease) and TG-rich lipoprotein particles. Significant (p < 0.001) reductions were also seen in low-density lipoprotein cholesterol (-25 to -35%) and non-HDL-C (-26 to -40%). Levels of HDL-C were increased (7-11%) in the simvastatin groups compared with placebo (p < 0.05 - < 0.001). CONCLUSION: The results of this study demonstrate the beneficial effects of simvastatin in patients with hypertriglyceridemia.

Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia.

The efficacy and safety of ezetimibe, a new cholesterol absorption inhibitor, was evaluated in this randomized, double-blind, placebo-controlled trial of 892 patients with primary hypercholesterolemia. After > or =2 weeks on the National Cholesterol Education Program (NCEP) Step I or a stricter diet and a 4- to 8-week single-blind placebo lead-in, patients with low-density lipoprotein (LDL) cholesterol 130 to 250 mg/dl and triglycerides < or =350 mg/dl were randomized 3:1 to receive ezetimibe 10 mg or placebo orally each morning for 12 weeks. The primary efficacy end point was the percent reduction in direct plasma LDL cholesterol from baseline to end point. A total of 434 men and 458 women (ages 18 to 85 years) received randomized treatment (666 ezetimibe 10 mg, 226 placebo). Demographics and baseline characteristics were similar between treatment groups. Ezetimibe significantly reduced direct LDL cholesterol by a mean of 16.9%, compared with an increase of 0.4% with placebo (p <0.01). Subgroup analysis indicated that response to ezetimibe was generally consistent across all subgroups, regardless of risk-factor status, gender, age, race, or baseline lipid profile. Ezetimibe effects on LDL cholesterol occurred early (2 weeks) and persisted throughout the 12-week treatment period. Compared with placebo, ezetimibe 10 mg also significantly improved calculated LDL cholesterol, apolipoprotein B, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and HDL(3) cholesterol (p <0.01). Ezetimibe was well tolerated. There were no differences in laboratory or clinical safety parameters, or gastrointestinal, liver, or muscle side effects from that of placebo. Ezetimibe 10 mg/day is well tolerated, reduces LDL cholesterol approximately 17%, and improves other key lipid parameters.

Efectividad y seguridad de las diferentes estatinas en el tratamiento de las dislipidemias / Efficacy and security of the different statins in the treatment of the dyslipidemias

Las estatinas o inhibidores de la 3-hidroxi 3-metilglutaril coenzima A, son los agentes hipolipemiantes de mayor uso en la actualidad. Su eficacia ha sido demostrada en múltiples estudios clínicos, y dependiendo del tipo de estatina usada y de su dosis, su eficacia en la reducción de LDL-colesterol va desde 13 por ciento hasta 61 por ciento. A través de múltiples estudios, las diferentes estatinas han demostrado ser muy seguras. Los efectos adversos, tales como daño hepático y daño muscular, son de muy baja frecuencia y generalmente reversibles. El uso concomitante de estatinas con otros agentes hipolipemiantes (niacina y resinas) es recomendado como segunda alternativa en el tratamiento de las dislipidemias severas.