FDA approval of lovastatin, the first statin (HMG-CoA reductase inhibitor)

Through the 1970s and early 1980s, clinicians had few effective tools for lowering LDL cholesterol. Bile acid sequestrants such as cholestyramine lowered LDL, but patients found them hard to tolerate. Niacin lowered lipids but carried substantial flushing and hepatotoxicity. The coronary risk associated with elevated LDL had been established by epidemiological data, including Framingham and the MRFIT study, but translating that knowledge into durable lipid reduction in daily clinical practice remained difficult.

The pharmacological answer came from an unexpected source: fungal metabolism. Akira Endo, a biochemist at Sankyo in Tokyo, inspired by Alexander Fleming's success with molds, began screening fungal culture broths in April 1971; after testing 3,800 strains he found a first inhibitor, citrinin. In July 1973 he isolated compactin from Penicillium citrinum, a blue-green mold from a rice sample collected at a grain shop in Kyoto, as a potent inhibitor of HMG-CoA reductase, the rate-limiting enzyme in the mevalonate pathway. In July 1976 Roy Vagelos, president of Merck Research Laboratories, obtained compactin samples and Sankyo's data under a confidentiality agreement, and Merck researchers then isolated a related compound, mevinolin, from Aspergillus terreus; in 1979 Endo found the same compound in Monascus ruber, and it became lovastatin. Merck filed its application in November 1986, and on August 31, 1987, the FDA approved lovastatin, sold as Mevacor, as the first statin.

In early clinical studies lovastatin lowered cholesterol sharply and was well tolerated, and long-term toxicity studies in dogs found no tumors. The drug's mechanism was clean: competitive inhibition of HMG-CoA reductase reduced hepatic cholesterol synthesis, which upregulated LDL receptor expression and increased clearance of LDL particles from plasma. Despite the lipid-lowering potency, the mortality question remained unanswered at the time of approval, as the FDA accepted surrogate endpoints for the initial indication.

The mortality evidence came in stages over the following decade. The Scandinavian Simvastatin Survival Study (4S) in 1994 showed that simvastatin reduced coronary death and total mortality in patients with established coronary disease. WOSCOPS in 1995 extended the benefit to primary prevention in men with hypercholesterolemia. These trials used second-generation statins, but they confirmed the mechanistic principle established by lovastatin. By the late 1990s, statin therapy had become standard of care for secondary prevention and for high-risk primary prevention.

By the 2010s, statins were among the most widely prescribed drugs in the world. Lovastatin itself was eventually superseded by more potent agents, including atorvastatin and rosuvastatin, but the compound's approval in 1987 opened the clinical and commercial path for the entire class. Endo, who had identified the foundational chemistry years before Merck's development program, received belated recognition through numerous international awards, including the Lasker-DeBakey Clinical Medical Research Award in 2008.