The U.S. Food and Drug Administration’s approval of the first member of the statin family of drugs, lovastatin, led to the discovery and production of a whole line of very effective cholesterol-lowering drugs. Extensive clinical trials with statins also ended the debate regarding the causative link between high blood cholesterol levels and coronary heart disease, and gave physicians a potent new weapon for the fight against coronary heart disease.
Cholesterol is a common component of animal cell membranes. It regulates membrane fluidity and is the starting material for the biosynthesis of steroid hormones, vitamin D, and bile salts. Unfortunately, excessive blood cholesterol concentrations cause cholesterol deposition underneath the lining of arteries, which eventually obstructs them and leads to coronary heart disease
More than one hundred years ago, German physician Rudolf Virchow demonstrated that the arteries of heart-attack patients were blocked with a yellowish, fatty substance. This condition was later termed “atheroma,” from the Greek word for “porridge.” In 1913, Nikolai Anitschkow, an experimental pathologist, induced atheroma in rabbits by feeding them purified cholesterol dissolved in sunflower oil. When he examined the atherosclerotic arteries of these cholesterol-fed rabbits under the microscope, Anitschkow observed cholesterol-laced, vascular lesions beneath the arterial linings that closely resembled those observed in human atherosclerosis. Rabbits fed with pure sunflower oil showed no signs of such lesions, and these data and those from several other experiments persuaded Anitschkow that a causative link existed between excessively high blood cholesterol levels and CHD.
After World War II, the standardized death rates caused by CHD in men increased dramatically in Western industrialized countries. Two studies initiated in the 1950’s, the Framingham Heart Study and the Seven Countries Study, established a solid correlation between high blood cholesterol levels and CHD-induced mortality. Furthermore, mutations in a single gene, the familial hypercholesterolemia (FH) gene,
In the early 1950’s, French physician Jean Cottet and American researchers Daniel Steinberg and Donald S. Fredrickson proposed a pharmaceutical approach to lowering blood cholesterol concentrations. Humans have the capacity to synthesize cholesterol from a molecule called acetyl-coenzyme A, which is the breakdown product of glucose or fatty acids. The researchers suggested that inhibition of cholesterol biosynthesis in the liver could decrease serum cholesterol levels and thus the risk of CHD. In 1953, researchers at the University of California, Berkeley, showed that steroid administration could suppress cholesterol biosynthesis in rat liver slices. In 1954, Cottet observed that agricultural workers who were exposed to an insecticide called phenylethylacetic acid became ill and had extraordinarily low blood cholesterol levels. Follow-up work by Steinberg, Fredrickson, and colleagues in 1958 demonstrated that the administration of delta-4 cholesterol also reduced blood cholesterol levels. Even though the toxicity of these compounds precluded their clinical use, these observations showed that cholesterol biosynthesis was a viable target for pharmaceutical inhibition.
Early attempts to lower blood cholesterol levels pharmacologically were disastrous. In 1959, the William S. Merrell Company
The rate-limiting step in cholesterol biosynthesis, which is heavily regulated in cells, is the conversion of beta-hydroxy beta-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, which is catalyzed by an enzyme called HMG-CoA reductase to form mevalonate. Because HMG-CoA is completely water soluble, its accumulation was not expected to cause any adverse side effects, so the inhibition of mevalonate synthesis through the inhibition of HMG-CoA reductase seemed to present an attractive target for drug research.
In 1973, at Sankyo Company
Endo’s results excited two researchers at the American pharmaceutical firm Merck & Company
Merck, therefore, suspended clinical trials on lovastatin and contacted the U.S. Food and Drug Administration (FDA). After consulting with experts in the cholesterol field, Vagelos presented his data to the FDA, and in July, 1982, the FDA gave Vagelos approval to continue clinical studies on lovastatin, but only with very high-risk patients who suffered from FH. Extensive long-term clinical studies in human patients and dogs subsequently showed definitively that lovastatin, which was eventually marketed under the brand name Mevacor, and all related compounds known as statins are not carcinogenic. Lovastatin was the first statin to be used in a critical large-scale clinical trial, the results of which were published in 1980.
In 1985, Vagelos was promoted to chief executive officer of Merck, and on August 31, 1987, after months of extensive testing, the FDA approved the sale of lovastatin. On that day, the battle against coronary heart disease acquired an effective new ally.
Lovastatin was the first of the group of drugs called statins that lower blood cholesterol levels. The success of lovastatin led to the discovery of even more potent statins. In 1991, the FDA approved Merck’s simvastatin (brand name Zocor), and slightly later that year, Bristol-Myers Squibb released pravastatin (brand name Pravachol). These were followed by the approval of Pfizer’s hugely successful atorvastatin (brand name Lipitor)
It would be difficult to overestimate the impacts that statins have had on the management of atherosclerosis, CHD, and stroke. Despite extensive evidence, the medical community was for a long time reluctant to accept the causative connection between high blood cholesterol levels and coronary heart disease. With the advent of statins, however, extensive clinical studies such as the 1994 Scandinavian Simvastatin Survival Study—the first truly large-scale, randomized, placebo-controlled, double-blind trial that tested the efficacy of statins—definitively showed that reduction of blood cholesterol levels reduced the risk of coronary heart disease and CHD-induced mortality. Statins soon became some of the most frequently prescribed drugs on the market in the United States, as they allowed physicians to treat aggressively even slightly elevated blood cholesterol levels, reducing the levels of heart disease in an increasingly obese population.
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Nelson, David L., and Michael M. Cox. Lehninger Principles of Biochemistry. 4th ed. New York: W. H. Freeman, 2005. Comprehensive textbook provides solid coverage of the basic aspects of cholesterol biosynthesis, metabolism, and lipoprotein particle trafficking. -
Steinberg, Daniel. “An Interpretive History of the Cholesterol Controversy, Part V: The Discovery of Statins and the End of the Controversy.” Journal of Lipid Research 47 (2006): 1339-1351. Brief historical perspective on the development of statins as therapeutic agents by a premier cholesterol researcher and scientific adviser to Merck. -
Tolbert, Jonathan A. “Lovastatin and Beyond: The History of the HMG-CoA Reductase Inhibitors. Nature Reviews Drug Discovery 2 (2003): 517-526. A Merck scientist presents a historical perspective on the discovery and development of statins and their importance. -
Vagelos, P. Roy, and L. Galambos. Medicine, Science, and Merck. New York: Cambridge University Press, 2004. Biography of Vagelos, who led Merck to develop lovastatin and become the largest manufacturer of pharmaceuticals in the late 1980’s and early 1990’s.
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