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Akira Endo, Discoverer of Life-saving Statin Drugs, Dies at 90

The Japanese biochemist who laid the foundation for the prevention of atherosclerotic cardiovascular disease, Akira Endo, died last week at the age of 90. In the early 1970s he began looking for a chemical that might be used to lower cholesterol and hopefully lower the risk of stroke, the disease that afflicted many of his family members.

Although he never received a Nobel prize, I think he should have for the discovery of the first statin.

I wrote about Endo in 2015 in a post addressing the use of red yeast rice to lower cholesterol levels (Red Yeast Rice: Let’s Lower Our Cholesterol With Unknown Amounts of a Statin Drug.) The post includes the following summary of how he found the earliest statin-type chemical in red yeast rice but goes on to elucidate why you shouldn’t use red yeast rice to lower your cholesterol.

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 from a natural source that becomes a safe and effective treatment that doctors can prescribe.

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.


“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, Endo found that


“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 another 10 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.

Endo, working separately and also in February 1979, isolated another statin (named 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 RYRand 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 red yeast rice 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 red yeast rice 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 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 variations in monacolin content and citrinin from batch to batch or bottle to bottle.

Problems With Alternative Medicine In General

“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 on hundreds of thousands of patients who have taken a similar dosage.

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

Skeptically Yours,

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