Abstract
The first four reviews in this series (Steinberg, D. 2004. J. Lipid Res. 45: 1583-1593; Steinberg, D. 2005. J. Lipid Res. 46: 179-190; Steinberg, D. 2005. J. Lipid Res. 46: 2037-2051; Steinberg, D. 2006. J. Lipid Res. 47: 1-14) traced the gradual accumulation of evidence, evidence of several different kinds, supporting the lipid hypothesis. They tracked the history from Anitschkow's 1913 classic work on the cholesterol-fed rabbit model to the breakthrough 1984 Coronary Primary Prevention Trial, the first large, randomized, double-blind primary intervention trial showing that decreasing blood cholesterol (using cholestyramine) significantly reduces coronary heart disease events. At that point, for the first time, decreasing blood cholesterol levels became an official national public health goal. Still, only a small fraction of patients at high risk were getting appropriate cholesterol-lowering treatment, and a number of important clinical questions remained unanswered. This final review in the series traces the early studies that led to the discovery of the statins and briefly reviews the now familiar large-scale clinical trials demonstrating their safety and their remarkable effectiveness in reducing coronary heart disease morbidity and mortality.
Highlights
The first four reviews in this series
In 1980, after Endo had already published several papers on the potency of compactin as an inhibitor, did the Beecham group explore its effects on cholesterol biosynthesis in vitro and in rats in vivo
There had been concern that treating hypercholesterolemia might reduce coronary heart disease risk, it might at the same time lead somehow to increases in mortality from other causes, not necessarily because of the decreased cholesterol levels per se but possibly from metabolic dysfunctions arising from other properties of the cholesterol-lowering agents
Summary
Years before the causal relationship between blood cholesterol level and coronary heart disease risk was widely accepted, there was already considerable interest in the possibility of using drugs to decrease cholesterol levels, especially in patients with markedly increased levels and strikingly high risk. Feeding the compound caused the accumulation of cholestanol [16], which was itself proatherogenic, and toxic side effects of the compound precluded clinical use [15] These early efforts failed to solve the problem, but they did at least spark interest in the possibility that cholesterol synthesis might be a legitimate pharmacologic target. This omission would turn out to be a major factor in the 1963 federal grand jury criminal indictment brought against the company and some of its employees. Fine’s excellent history of this scandal [21] for more information
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