ABSTRACT
By 1970, epidemiologic studies had shown that increased levels of blood cholesterol were causally related to an increased risk of coronary heart disease.1,2 The Framingham Study,2 the most famous of these surveys, which started in 1949, showed that the risk of coronary heart disease (CHD) rose progressively with an increase in the level of blood cholesterol. Several clinical studies suggested that the lowering of cholesterol levels by the ingestion of low-fat diets or by treatment with lipid-lowering drugs would reduce the incidence of coronary heart disease.3-5 At the beginning of the 1970s, there were some reasons to believe that levels of blood cholesterol could be reduced by inhibiting 3hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-controlling enzyme in the cholesterol synthetic pathway.6,7
In 1971, we began our search for microbial products that would inhibit HMG-CoA reductase and that might therefore reduce levels of plasma cholesterol in humans. We postulated that some micro-organisms would produce such novel compounds, and this possibility fascinated us because such products had not been isolated previously. These studies led to the discovery of a potent, low-toxicity reductase inhibitor, named mevastatin (formerly called compactin or ML-236B),8 the prototype of the statins. Subsequently, we elucidated the biochemical mechanisms of action of mevastatin,9,10 and by the end of the 1970s we had shown that mevastatin markedly reduced levels of total and low-density lipoprotein (LDL) cholesterol in both experimental animals and patients with primary hypercholesterolaemia.11−13 These findings apparently stimulated the worldwide development of mevastatin analogs (statins) in the 1980s and, by 1991, three statins-lovastatin (formerly called mevinolin or monacolin K), simvastatin and pravastatin-had been approved and marketed in the USA and many other countries.14,15 Since then, three statins that were chemically synthesized have also been introduced to the market.16 All of these statins have been well established as effective and safe cholesterol-lowering agents and have been used by millions of patients.17,18 Several landmark clinical trials with statins have recently demonstrated that lipid-lowering therapy reduces cardiovascular morbidity and mortality in both primary and secondary prevention.19−21 This chapter will primarily focus on the history of the discovery and development of mevastatin, the prototype of the statins, and lovastatin, the first to be marketed.
