May 1st, 2015

Red Yeast Rice: Let’s Lower Cholesterol with Unknown Amounts of a Statin

CardioExchange welcomes this guest post from clinical cardiologist Anthony Pearson. This piece originally appeared on his blog, The Skeptical Cardiologist.

Over the years I’ve had a number of patients tell me that they prefer to take over-the-counter (OTC) dietary supplements containing “natural” cholesterol lowering ingredients rather than the statin drug I have prescribed.

Red yeast rice (RYR) is a common ingredient in these supplements and is promoted widely and enthusiastically across the internet and in supplement or natural-food stores for the purpose of lowering cholesterol and heart disease risk.

RYR has been used for centuries in China for coloring, food, and medicine. It is made by fermenting red rice with a specific type of yeast (Monascus purpureus) and contains chemicals that are similar to prescription statin medications. One of these, called monacolin K, is chemically identical to the statin drug lovastatin (brand name Mevacor).

The History of Statin Drug Development

The history of the discovery and isolation of lovastatin, the first FDA-approved statin, is worthy of a digression here as I think it illustrates the process of discovery, isolation, and characterization of a chemical that becomes a safe and effective treatment.

Akira Endo, whose research over decades was crucial to discovering statins, writes that he was inspired by Alexander Fleming, who discovered penicillin in the blue-green mold belonging to the genus Penicillium in 1928. He writes: “Although no metabolites that inhibited any enzymes involved in cholesterol synthesis had been isolated previously, I speculated that fungi like molds and mushrooms would produce antibiotics that inhibited HMG-CoA reductase. Inhibition of HMG-CoA reductase would thus be lethal to these microbes.”

Endo began analyzing thousands of molds and fungi for biologically active chemicals that would inhibit HMG-CoA reductase. In 1971, after studying 3800 different strains of fungi, he found a promising candidate: citrinin. Unfortunately, “Citrinin strongly inhibited HMGCoA reductase and, furthermore, lowered serum cholesterol levels in rats. However, the research was suspended because of its toxicity to the kidneys.”

Endo spent 10 more years isolating another promising HMG-CoA reductase inhibitor — compactin — from mold and studying it in rats and other animals. Compactin demonstrated marked cholesterol-lowering properties in dogs and monkeys and in the few humans who received it, but the pharmaceutical company he worked for shut down the project after it appeared that, in doses 200 times what were considered appropriate, it increased lymphoma risk in dogs.

The large pharmaceutical company Merck got wind of Endo’s studies with compactin, studied his data, and realized the potential of similar but safer HMG-CoA reductase inhibitors. Drugs that inhibited HMG-coA reductase were now being termed statins. Merck set out to find its own statins and in February 1979 isolated a statin very similar to compactin in chemical structure, called mevinolin, from the fungus Aspergillus terreus.

Working seperately, Endo also isolated another statin in February 1979 — monacolin K — from cultures of Monascus ruber (RYR). In the fall of the same year, it was confirmed that monacolin K and mevinolin were the same compound (later both changed to lovastatin).

The drug showed dramatic activity in lowering LDL cholesterol, with very few side effects. This led Merck to begin large-scale clinical trials of lovastatin in patients at high risk and long-term toxicity studies in dogs in 1984. The drug dramatically reduced cholesterol levels and was well tolerated. No tumors were detected. In 1987, Merck gained FDA approval  and lovastatin became the first commercial statin.

Since then, six other statin drugs, some of which are synthesized in the laboratory rather than isolated from mold, have been approved for human therapy. These drugs have prevented thousands of heart attacks and contributed to the dramatic drop in cardiovascular deaths seen in developed countries over the last 30 years.

RYR and Cholesterol Lowering

This brings us back to RYR and its ability to lower cholesterol. Small studies using a version of RYR that contained lovastatin have demonstrated a reduction in cholesterol compared to placebo. However, because many RYR supplements contained lovastatin (also called monacolin), in May 1998 the FDA ruled that Cholestin (the RYR product used in the studies showing cholesterol-lowering benefit) was not a dietary supplement but an unapproved drug.

As a result, Pharmanex removed RYR from Cholestin. Since that ruling, the FDA has written warning letters to several other dietary supplement manufacturers to remove drug claims or eliminate RYR with high lovastatin levels from their products, including Heart and Cholesterol (Mason Vitamins, Miami Lakes, Florida),  Cholestrix (Sunburst Biorganics, Baldwin, New York), Red Yeast Rice and Red Yeast Rice/Policosanol Complex, and Red Yeast Rice (Nature’s Way Products, Inc.)

A study in 2010 found levels of monacolins varying one-hundred fold in 12 RYR preparations available commercially (total monacolins (0.31-11.15 mg/capsule), monacolin K (lovastatin) (0.10-10.09 mg/capsule), and monacolin KA (0.00-2.30 mg/capsule).

Even more worrisome was that four products had elevated levels of citrinin. You remember citrinin, don’t you? That is the chemical that Endo initially identified as a candidate for a cholesterol-lowering drug but rejected because it was causing kidney failure in his rats.

Because of limited government oversight and variable manufacturing processes, one can also expect that the same manufacturer will have marked variation of monacolin content and citrinin from batch to batch or bottle to bottle.

Problems With Alternative Medicine In General

These problems with RYR supplements are typical of all supplements. As the the authors wrote: “Our results highlight an important issue with red yeast rice and many other alternative medicines: the lack of standardization of active constituents. Standardization of ingredients is difficult for several reasons: (1) There are variable growth and/or culture conditions and differences in harvesting and processing among manufacturers; (2) medicinal agents from natural sources are complex substances with many chemical constituents, many of which have unclear roles in their pharmacologic activity; and (3) different manufacturers may standardize products to amounts of 1 or 2 chemicals thought to be active ingredients, while other constituents are not standardized and may also have biologic and pharmacologic activity.”

One has to ask, given this background: Why would a patient choose to take a “natural” OTC supplement containing an unknown amount of both a) effective cholesterol-lowering chemicals and b) potentially toxic extraneous chemicals over the precisely formulated, carefully regulated, fully studied, pure statin drug available by prescription? It’s especially baffling to me when one considers that lovastatin comes from RYR. Thus it would have to be considered “natural.”

Akira Endo spent decades carefully identifying the effective and safe chemical portion of RYR. It is now available as a generic costing pennies per pill. We know exactly how many milligrams you are consuming. We know what benefits to expect and what side effects can occur based on studies in hundreds of thousands of patients who have taken a similar dosage.

You are much better off taking the prescribed statin drug than RYR.

5 Responses to “Red Yeast Rice: Let’s Lower Cholesterol with Unknown Amounts of a Statin”

  1. Jeff Dickey, MD says:

    Your rhetorical question, “Why would a patient choose to take a “natural” OTC supplement containing an unknown amount of both a) effective cholesterol-lowering chemicals and b) potentially toxic extraneous chemicals over the precisely formulated, carefully regulated, fully studied, pure statin drug available by prescription?” The answer is rather simply implied by stories like the other one in today’s email; we may have lost some trust by using a drug for 200 years before we realized “there was a 21% increase in the relative risk of death in people taking digoxin”.
    I don’t prescribe red yeast rice, I recommend prescription statins, but if you want to know why people do prefer red yeast rice, it’s because we have lost some trust along the way by studying surrogate rather than definitive end points; and we still do.
    We used sulfanylureas in diabetes for years before we started suspecting increased cardiac risks. We tried flecainide for arrhythmia after myocardial infarction before we realized it increased mortality.
    So I don’t recommend ‘natural’ treatments with non-standardized dosing and possible significant toxicities. But if you want to know why people do, you need look no further than our own history of prescription drug toxicity.

  2. Q: Why would a patient choose to take a “natural” OTC supplement containing an unknown amount of both a) effective cholesterol-lowering chemicals and b) potentially toxic extraneous chemicals over the precisely formulated, carefully regulated, fully studied, pure statin drug available by prescription?

    A: Medicine has lost credibility with many consumers. Statins have been marketed to consumers leaving a perception that they are all you need to stop heart attacks. Most people are shocked to see a paltry 25% reduction in heart attacks and a 17% reduction in coronary death in the Heart Protection Study.

    Physicians have been taught that statins are safe and effective. The late finding of increased risk of diabetes, and a significant increased risk of muscle toxicity associated with exercise catches us off guard. Our patients have been telling us that they hurt and we tell them to keep taking it because their muscle enzymes are not too elevated.

    When “conventional medicine” loses credibility, alternative options look good.

    In addition, thought leaders support the position that fish oil is of no value, vitamin D is of no value, niacin is of no value. Further interrogation of the evidence brings these positions into serious question. Another reason for conventional medicine to not be trusted.

    We continue to to 10 million nuclear stress tests and place tens of thousands of elective stents every year despite overwhelming evidence that it provides no benefit other than quick symptom relief.

    Although I agree that RYR has potential for significant risk, I have seen no studies where it demonstrated risk an a couple of studies where it was found to be safe.

    When we learn to put complete honesty above profits and patient care above pride, we can re-earn credibility. Until then, why should we expect consumers to respect our opinions on RYR?

  3. Antonio H. Reis, Ph.D says:

    I completely agree with Dr Blanchet. More, the strategy of putting all the focus on lowering cholesterol was wrong, not substantially reduced deaths by heart disease, and is today quite discredited by the general public. This is made worse by the fact that the negative effects of statins are usually undervalued. New and more comprehensive approaches are needed on preventing cardiovascular disease.
    Akira Endo might have been inspired by the history of the development of antibiotics. However, the comparison is not at all possible because antibiotics have a success story, which is very far from happening with statins.

  4. Joseph Wildman, MD says:

    1. For some reason, some patients tolerate RYR well despite intolerance of statins.
    2. Unlike other “supplements”, here we have a measurable endpoint: chol, LDL levels
    3. Have seen no actual reports of toxicity/adverse effects.
    4. Suspect that the FDA’s antipathy is based on obedience to their corporate masters, rather than genuine concern for pts.
    5. THEREFORE: Why NOT use RYR in selected pts???

  5. Regina Druz, MD says:

    Dear Dr. Pearson, and Cardioexchange,
    I am shocked to see such a. based post selected for our audience. I completely agree with the comments posted by all of the responders on this discussion so far. For starters, let’s stop calling medicine ” natural”, and state explicitly that natural compounds of medicinal value exist. Drop the quotations marks. Secondly, RYR contains several types of compounds, some with statin-like properties. The preparations and standardization are an issue yet less so if one chooses to use professional grade supplements, not available on any store shelves. Obviously, the author didi not bother to acknowledge this. Finally,, bear in mind that large, randomized controlled trials will never happen for medicinal substances. Registry type data, coupled with genetic reporting, will make a difference. I use both statins and medicinal foods and supplements as an integrative cardiologist in minor active, in a variety of protocols that follow principles of functional medicine. I compel those of you with an interest in this area to communicate more with your patients, learn how they came about to use these compounds, and track their responses scientifically. On calling the functional medicine alternative- to what? To our annual spending of nearly $3 trillion while seeing the highest rates of obesity and chronic diseases? The so called “alternative” will eliminate about 80% of this burden. I use it myself, and practice it daily.