Extensive epidemiologic studies performed in many countries have shown that increased blood cholesterol levels, or, more specifically, increased levels of LDL-cholesterol, are causally related to an increased risk of coronary heart disease. Coronary risks rises progressively with an increase in the cholesterol level, particularly when cholesterol levels rise above 200 mg/dl (1, 2). There is also substantial evidence that lowering total and LDL-cholesterol levels will reduce the incidence of coronary heart disease (2).

In 1971 we started a project to search for microbial metabolites that would inhibit HMG-CoA reductase, the rate-limiting enzyme in the synthesis of cholesterol. We hoped that the suppression of de novo cholesterol synthesis in the body by inhibiting HMG-CoA reductase would reduce plasma cholesterol levels in humans. These studies led to the discovery of a potent reductase inhibitor, named mevastatin (formerly called ML-236B or compactin)(3). Subsequently, we elucidated the biochemical mechanisms of action of mevastatin (4, 5) and by 1980, had shown that mevastatin markedly lowers the levels of LDL-cholesterol in both experimental animals and humans (6-8). These findings stimulated the world-wide development of mevastatin analogues in the 1980s and, by 1990, three drugs-lovastatin (formerly called mevinolin), simvastatin, and pravastatin-had been approved and marketed in many countries (9, 10). These drugs have been well established as effective and safe cholesterol-lowering drugs and are used by many patients. Beneficial effects from their administration in patients with coronary heart disease are being observed (11).