Dr Jonathan Tobert, University of Oxford, UK, recalls the landmark statin research by Dr Akira Endo that has saved countless lives.
Akira Endo (biochemist). (2024, July 16), in Wikipedia.
Akira Endo died on June 5 at the age of 90. He worked as a microbiologist in Japan and is universally recognised as the discoverer of statins (more formally inhibitors of HMG-CoA reductase) that could be used to reduce LDL-cholesterol (LDL-C). The medical importance of his discovery is arguably comparable with Fleming’s discovery of penicillin.1
Endo's parents were farmers in a mountainous area of north-eastern Japan. His grandfather took young Akira on walks to find mushrooms in the forests, and this fuelled his lifelong interest in fungi. In the 1970s, Endo was searching for agents with useful antimicrobial activity, but no HMG-CoA reductase inhibitor has been found useful for this purpose. The conversion of hydroxymethylglutarate (HMG) to mevalonate is the rate-limiting reaction in the 30-step cholesterol biosynthesis pathway. In 1976, Endo identified compactin, a potent inhibitor of HMG-CoA reductase, in a fermentation broth of penicillium citrinum.2 Endo quickly appreciated that compactin, an agent inhibiting the rate-limiting step in the cholesterol biosynthesis pathway, might lower plasma lipids. This was not lost on others, and compactin was found to lower plasma cholesterol in several animal species, but not the rat. Beecham's Laboratories, a UK company, had been interested in HMG-CoA reductase inhibitors, but the rat data deterred them from further activity. Massive induction of HMG-CoA reductase in rat liver was subsequently identified as the cause of non-responsiveness to compactin in rodents.
The mechanism of action of statins is not simply due to a reduction in cholesterol biosynthesis. Hepatocytes and other cells respond to a reduction in intracellular cholesterol by inducing the LDL receptor on the cell surface. This upregulation increases LDL uptake into the liver and thus lowers circulating LDL-C.3 These pathways were elucidated in detail by Brown and Goldstein, who received a Nobel Prize for their discoveries.
In collaboration with Hiroshi Mabuchi, Sankyo and others, Endo was involved with studies of the ability of compactin to reduce LDL-C in patients with familial hypercholesterolaemia, and substantial lipid-lowering efficacy was shown. At about the same time, Al Alberts and colleagues at Merck Research Laboratories discovered a potent HMG-CoA reductase inhibitor in a fermentation broth of aspergillus terreus derived from a soil organism in Spain4 – by a stroke of good fortune in only the 18th broth studied. Alberts named this compound mevinolin, and it was subsequently renamed lovastatin, its current name. Healthy volunteer trials began in 1980, and these clearly demonstrated the efficacy of lovastatin, with a 40% reduction in LDL-C at the maximal 80 mg dose, and no detectable adverse effects.5
Larger clinical trials in patients with hypercholesterolaemia were scheduled to start when Merck learned that Sankyo had suddenly stopped clinical trials with compactin for unknown reasons.1 Merck immediately suspended its own clinical development programme in September 1980, but continued animal toxicology studies, which did not reveal any unexpected adverse effects. In 1983, Roy Vagelos, the head of research and later CEO at Merck, made the difficult decision to resuscitate the lovastatin programme.1, 5 Sankyo subsequently resumed clinical research efforts with another statin, pravastatin.
Variation in patent laws in different countries meant that lovastatin had patent protection only in the US and a few other countries. Worldwide patent protection is always desirable from the point of view of a manufacturer, and Merck had discovered a semisynthetic derivative of lovastatin named simvastatin. This did have patent protection worldwide, so simvastatin became the focus of the statin clinical trials performed by Merck. Lovastatin was granted regulatory approval in 1987 and simvastatin in 1988-1989. In 1994 the landmark 4S study with simvastatin in patients with coronary heart disease and hypercholesterolaemia showed unequivocally that a statin could safely reduce cardiovascular mortality,6 which greatly increased physician confidence and statin usage. Other statins followed, most importantly atorvastatin, which today is the most widely prescribed statin.
Statins have been prescribed for hundreds of millions of people worldwide, preventing countless unnecessary deaths. Today all statins are generic and cost very little. No drug class has been more thoroughly evaluated for safety and efficacy, and their ability to prevent myocardial infarction and stroke is indisputable. Drug discovery and development is a large team effort with many disciplines involved, but the statin story all started with Akira Endo. He was honored with several well-deserved awards, notably the Lasker-DeBakey Prize in 2008.
Many believe he deserved the Nobel Prize.
Jonathan Tobert MD PhD is a clinical pharmacologist and trialist. He led the early clinical trials with lovastatin, the first marketed statin, at Merck, and has devoted most of his career to the safety and efficacy of statins. After retiring from Merck, he became an Academic Visitor at the Nuffield Department of Population Health, University of Oxford, UK. He has published several papers on statin adverse effects, including the role of the nocebo effect in statin intolerance.
References
- Thompson GR. Resolving the cholesterol controversy: the scientists who proved the lipid hypothesis of causation of atherosclerosis and coronary heart disease. London: World Scientific Publishing Europe; 2023
- Endo A. A historical perspective on the discovery of statins. Proceedings of the Japan Academy, Series B. 2010;86(5):484-93
- Bilheimer DW, Grundy SM, Brown MS, Goldstein JL. Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes. Proc Natl Acad Sci U S A. 1983;80(13):4124-8
- 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 A. 1980;77(7):3957-61
- Tobert JA. Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors. Nature Reviews-Drug Discovery. 2003;2(7):517-26
- Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). The Lancet. 1994;344:1383-89
