Lasker award for the discoverer of statins

Br J Cardiol 2008;15:294–5 Leave a comment
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The announcement that Akira Endo has won the 2008 Lasker-DeBakey Clinical Medical Research Award is a fitting tribute to the man who discovered the first statin. The remarkable ability of these compounds to lower cholesterol has revolutionised medical practice, boosted the profits of the pharmaceutical industry and improved the health of millions. The story of this discovery illustrates how Endo’s single-minded pursuit of an idea changed the course of history, an achievement that has now been recognised by his peers in the scientific community.

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Cholesterol and cardiovascular disease

Cholesterol has the Jekyll and Hyde characteristics of being both essential to life as a constituent of the body’s cells and of being the prime initiator of atherosclerosis, a process characterised by the formation of cholesterol-rich plaques in arteries. This disorder is the major cause of cardiovascular disease, mainly coronary heart disease and stroke, from which 11 million people die in the world each year. The most common single cause of death in Britain, its eradication is given a high priority by the government.

Numerous studies have identified cholesterol, specifically low-density lipoprotein (LDL) cholesterol, as a risk factor for cardiovascular disease – the higher the level in plasma, the greater the risk. Lowering plasma cholesterol by dietary means in the 1950s gave disappointing results, which led to the development of drugs such as clofibrate and cholestyramine that reduced cholesterol more effectively than diet but had side effects. The premise that lowering cholesterol would reduce cardiovascular disease was tested in several trials during the 1960s and 1970s, but the results were inconclusive, and generated scepticism among cardiologists.

Discovery of the first statin

In 1971, Akira Endo, a Japanese microbiologist working for the pharmaceutical company Sankyo, started searching for microbial metabolites that would inhibit hydroxymethylglutaryl co-enzyme A (HMG-CoA) reductase, the key enzyme of cholesterol synthesis. His belief that this would provide a novel means of lowering plasma cholesterol was vindicated when, after two years of testing more than 6,000 microbial strains, he and his colleagues isolated a potent inhibitor of HMG-CoA reductase from Penicillium citrinum.1 Known as compactin, this compound became the first HMG-CoA reductase inhibitor or statin to be used in humans.

Endo’s premise that inhibition of HMG-CoA reductase would lower plasma cholesterol was based on Goldstein and Brown’s Nobel Prize-winning discovery that the inherited disorder familial hypercholesterolaemia (FH) was characterised by defective regulation of HMG-CoA reductase due to a deficiency of LDL receptors. Endo and they showed that compactin was a potent inhibitor of cholesterol synthesis in cultured cells both from normal subjects and patients with FH.2 Studies in rats were disappointingly negative3 but compactin lowered serum cholesterol levels in dogs4 and monkeys. The first clinical studies with the drug were performed in 1980 and showed impressive reductions in LDL-cholesterol in FH patients.5 However, Sankyo abruptly suspended their clinical trial programme at that stage for undisclosed reasons and it was never licensed.

Merck’s role

Endo had collaborated with the US drug company Merck several years previously by providing them with samples of compactin. In 1980, researchers at Merck isolated a second HMG-CoA reductase inhibitor, from Aspergillus terreus, which was initially called mevinolin6 but became known as lovastatin. Simultaneously, Endo, now having left Sankyo, isolated the same compound from a different mould, naming it monocolin K.7 Merck proceeded with the clinical development of lovastatin and in 1987 it became the first HMG-CoA reductase inhibitor to be licensed in the USA, although patent constraints precluded it from being marketed in the UK. Other statins soon followed including pravastatin, which was derived from compactin, simvastatin, which was derived from lovastatin, fluvastatin, the first synthetic HMG-CoA reductase inhibitor, atorvastatin, currently the world’s best selling drug, and rosuvastatin, the latest and most potent of these compounds to be licensed.

The statin trials

During the 1990s, statins were tested in a series of clinical trials that established unequivocally that lowering LDL-cholesterol resulted in significant decreases in cardiovascular and total mortality, with remarkably few side effects. As a result, these drugs are now routinely used to treat and prevent cardiovascular disease throughout the world. They have revolutionised the practice of cardiology and it has been estimated that one third of adults in the USA and UK would benefit from taking them. Other advances in therapy make it difficult to quantify the precise extent of their contribution to the recent decline in cardiovascular disease, but the ability of the newer compounds to lower LDL-cholesterol by 50–60% could halve the risk of future heart attacks and strokes.

A first in the prevention of cardiovascular disease

Almost a century and a half ago, Mark Twain summed up the essence of research in these words: “Discovery! To know that you are walking where none others have walked; that you are beholding what human eye has not seen before… to discover a great thought, an intellectual nugget, right under the dust of a field that many a brain-plough has gone over before… To be the first – that is the idea.” Akira Endo’s discovery of the cholesterol-lowering properties of compactin over 30 years ago was undoubtedly a first in the treatment of atherosclerotic cardiovascular disease, as was Alexander Fleming’s discovery half a century earlier of the antibiotic properties of penicillin. Fleming, Florey and Chain were awarded the Nobel Prize for that discovery in 1945, which coincidentally was the year when the Lasker awards were inaugurated. Since then almost half the winners of the Nobel Prize for Medicine or Physiology have previously received a Lasker award, which illustrates the latter’s significance both as an achievement in itself and as a pointer to further acclaim.

Conflict of interest

None declared.

Gilbert R Thompson Emeritus Professor of Clinical Lipidology

Metabolic Medicine, Imperial College, Hammersmith Hospital, London, W12 0NN


  1. Endo A, Kuroda M, Tanzawa K. Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity. FEBS Lett 1976;72:323–6.
  2. Brown MS, Faust JR, Goldstein JL et al. Induction of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in human fibroblasts incubated with compactin (ML-236B), a competitive inhibitor of the reductase. J Biol Chem 1978;253:1121–8.
  3. Endo A, Tsujita Y, Kuroda M, Tanzawa K. Effects of ML-236B on cholesterol metabolism in mice and rats: lack of hypocholesterolemic activity in normal animals. Biochim Biophys Acta1979;575:266–76.
  4. Tsujita Y, Kuroda M, Tanzawa K et al. Hypolipidemic effects in dogs of ML-236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Atherosclerosis 1979;32:307–13.
  5. Yamamoto A, Sudo H, Endo A. Therapeutic effects of ML-236B in primary hypercholesterolemia. Atherosclerosis 1980;35:259–66.
  6. Alberts AW, Chen J, Kuron G et al. Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci U S A1980;77:3957–61.
  7. Endo A, Monacolin K. A new hypocholesterolemic agent produced by a Monascus species. J Antibiot 1979;32:852–4.