Key Takeaways
The first statin was isolated from a blue-green mold found on rice, a close cousin of the mold that spoils citrus fruit, not designed in a lab.
Akira Endo screened over 6,000 fungal strains before isolating compactin from Penicillium citrinum in 1973.
Compactin never reached the market, but it led directly to lovastatin, the first FDA-approved statin, in 1987.
Every medical student learns that HMG-CoA reductase as the rate-limiting step of cholesterol synthesis. But only a few learn that the drug class built around inhibiting it was not designed in a lab at all. It was found growing on spoiled rice at a Kyoto grocery shop, by a scientist, named Akira Endo who suspected fungi might already be fighting the same biochemical battle he hoped to win.
Endo grew up on a farm in rural Japan, fascinated by fungi and moulds from childhood.1 He studied agricultural chemistry at Tohoku University and came across the biography of Alexander Fleming, which convinced him of his intention to discover a potential medicinal agent within mould2. He was employed by Sankyo in 1957, and his first assignment was isolating a fungal pectinase used to clarify wine.3 However, a 2 year period Albert Einstein College of Medicine in New York, from 1966 to 1968, changed his priorities back. Witnessing how common heart disease occurred there, convinced him of the value of a cholesterol-lowering drug. Back in Tokyo, he hypothesized that fungi, competing with other microbes for the same pathway humans use to build cholesterol, might produce natural HMG-CoA reductase inhibitors as a chemical defence1.
From 1971, Endo and colleague Masao Kuroda screened roughly 3800 fungal broths, tracking how well each blocked cholesterol formation in rat liver homogenates1. Over two years, the team examined more than 6,000 fungal strains, mostly without success3. In midsummer 1972, one broth worked: a blue-green mould grown on rice from a Kyoto shop, closely resembling the mould that spoils citrus fruit. Endo named the compound ML-236B, which was later renamed into compactin1. It should be noted that Penicillin citrinum is the same genus from which Fleming discovered penicillin 40 years earlier1.
Because of its structural similarity to mevalonate (product of HMG-CoA reductase), Compactin is an effective, reversible, competitive inhibitor of this enzyme of cholesterol synthesis1. Decrease in intracellular cholesterol levels leads to upregulation of hepatic LDL receptor. This causes extraction of more LDL from bloodstream, thus decreasing levels of plasma LDL-C, but not HDL-C6. This principle was discovered by Michael Brown and Joseph Goldstein, who received Nobel Prize for their findings that helped explain Endo’s practical observation.
Compactin lowered cholesterol in chickens, dogs, and monkeys, though not in rats, complicating early development. In 1980, Endo and physician Akira Yamamoto reported a 27 percent LDL-C reduction in patients with severe hypercholesterolemia1. Sankyo halted trials that year over concerns that high-dose compactin might cause lymphoma in dogs, though the tested dose exceeded any realistic clinical dose3. Merck had obtained the compactin findings from Sankyo, and in 1979 a team led by Alfred Alberts independently isolated a similar compound from Aspergillus terreus, renamed it lovastatin. Lovastatin was FDA-approved in 1987 as the first commercial statin1,3.
Akira Endo did not receive a Nobel Prize. He received the Japan Prize (2006), the Lasker-DeBakey Award (2008), and the Gairdner International Award (2017)2,3. Brown and Goldstein who received the Nobel Prize in 1985, said the millions of lives extended through statin therapy are all owed to Akira Endo1. Endo died in Tokyo on June 5, 2024, aged 901,2.
Atherosclerotic Cardiovascular Disease (ASCVD) in Indians tends to occur in younger population, with only modest hypercholesterolemia, and follows a more severe course than in Western populations4. The Lipid Association of India recommends more aggressive LDL-C goals than US or European guidelines, alongside non-HDL-C as a co-primary target12. Several statins also reach roughly 1.5 to 2.3 times higher plasma levels in Asian patients than others, relevant when initiating or adjusting the therapy4. Statins remain widely available and inexpensive in India, making LDL-C lowering a cost-effective ASCVD prevention tool, though therapy should always be under a physician guidance.
The statin story began not with a hypothesis about drug design but with a scientist willing to test thousands of ordinary fungal cultures for one useful result. That patience underlies one of the most prescribed, evidence-backed drug classes in cardiovascular medicine today.
Goldstein, Joseph L., and Michael S. Brown. "Akira Endo, Who Discovered a 'Penicillin' for Heart Attacks (1933 to 2024)." Proceedings of the National Academy of Sciences 121, no. 40 (2024): e2416550121. https://doi.org/10.1073/pnas.2416550121 .
Catapano, Alberico L., Angela Pirillo, and Lale Tokgözoğlu. "In Memoriam: Akira Endo." European Heart Journal 45, no. 35 (2024): 3199–3200. https://doi.org/10.1093/eurheartj/ehae470 .
Chester, Adrian, and Ahmed El Guindy. "From Fleming to Endo: The Discovery of Statins." Global Cardiology Science and Practice 2021, no. 4 (2021): e202132. https://doi.org/10.21542/gcsp.2021.32 .
Duell, P. Barton, Vimal Mehta, Devaki Nair, Sundeep Puri, and Rashmi Nanda. "Proposed Low-Density Lipoprotein Cholesterol Goals for Secondary Prevention and Familial Hypercholesterolemia in India with Focus on PCSK9 Inhibitor Monoclonal Antibodies: Expert Consensus Statement from the Lipid Association of India." Journal of Clinical Lipidology 14, no. 2 (2020): 170–186. https://doi.org/10.1016/j.jacl.2020.01.010 .