Lovastatin

If he had to rely on a single measurement to predict how likely a patient is to suffer from heart disease, Chris K. Y. Wong, a cardiologist in private practice in Hong Kong's Central District, says he would choose blood cholesterol. "The higher the cholesterol, the higher the possibility," the Glasgow-trained medical specialist says.

Cholesterol-lowering drugs, like Merck's lovastatin, are a huge industry. Pfizer's Lipitor is the world's top drug, with sales last year of more than $10 billion. And as a class, cholesterol- and triglyceride-lowering drugs were the world's top category in 2004, with sales exceeding $30 billion, according to IMS Health, a pharmaceutical market research firm.

Heart disease is a leading cause of death, and the problem is growing. In the U.S., Wong says, close to 30 million people are being treated for cardiovascular diseases and 2 million Americans suffer heart attacks annually. Abroad, heart ailments are becoming common in countries with fast -growing economies like India and China as diets become richer, lifestyles turn sedentary, and stress levels rise.

Statin drugs "are one of the cornerstones in the prevention of both primary and secondary heart diseases," Wong says. Secondary heart diseases, Wong explains, are those that occur after a patient has suffered a heart attack or has had heart surgery. Studies have shown that lowering cholesterol is so effective in preventing heart disease that even people with no history of cardiovascular problems could benefit from taking statins, Wong reports. Last summer, cardiologists in the U.K. debated the benefits of adding statins to the water supply.

Akira Endo, a research scientist at Sankyo Pharmaceutical in Japan, discovered statins in 1971. The drugs work by inhibiting the enzyme HMG-CoA reductase, which is the main regulator of cholesterol synthesis. Sankyo went on to develop the first statin drug, mevastatin, but never introduced it on the market. Instead, working with Merck, it codeveloped another statin, lovastatin, launched in the U.S. in 1987. Pfizer launched Lipitor in 1997.

Statins are perhaps the most intensely researched drug category and are still one of the most promising types of pharmaceuticals. Recent studies have shown that they may be effective at preventing Alzheimer's disease (C&EN, Feb. 21, page 38) and may fight multiple sclerosis. Why this is so remains the subject of numerous hypotheses.

Meanwhile, questions about statins' heart-disease-fighting effect remain inconclusively answered. How do low-density lipoproteins--generally known as LDL cholesterol or "bad" cholesterol--cause atherosclerosis, and how does a high level of high-density lipoproteins--known as HDL cholesterol or "good" cholesterol--reduce clogging of the arteries? Statins lower LDL while raising HDL.

Not everyone agrees that high LDL cholesterol is the actual cause of atherosclerosis. While Nobel Laureates Joseph L. Goldstein and Michael S. Brown insist that studies have proven this fact beyond a doubt, Kilmer S. McCully, a researcher at the Veterans Administration hospital in Providence, R.I., is gaining a following for his theories that the amino acid homocysteine is the actual culprit. Cholesterol, McCully claims, transports homocysteine to the heart, but it does not lead to plaques that narrow arteries. To reduce heart disease, it would be more effective to reduce homocysteine in the blood, he asserts.

Cholesterol is an essential blood component that is present in all body cells. In particular, cholesterol serves to build the cell membranes of the nerves and is found along the nervous system. The body acquires cholesterol through diet or creates it in the liver. Critics of statin drugs claim that because cholesterol is essential to life, it is perilous to artificially alter its level in the blood.

Statins do induce a number of undesirable side effects in a minority of patients. Former astronaut Duane E. Graveline wrote a book in which he blamed Lipitor for episodes of memory loss. Statins may also set off muscle disorders such as myositis or rhabdomyolysis. Myositis may cause no more than muscle pain, but rhabdomyolysis is a form of muscle breakdown that can be fatal. Bayer agreed to remove its statin Baycol from the market in 2001 after it was linked to more than 50 cases of rhabdomyolysis.

It will take decades and several large-scale studies before statins are fully understood, Wong says. For the time being, cardiologists are satisfied that the drugs have proven to be effective at preventing heart disease.

Drug companies have a vested interest in further researching statins. If a statin drug proves to be effective in preventing or curing a disease like Alzheimer's, it could be worth tens of billions of dollars.

Lovastatin

Name
◾ (2S)-2-Methylbutanoic acid
(1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]-ethyl]-1-naphthalenyl ester

CAS Registry
◾ 75330-75-5

Other Names
◾ Mevacor

Introduced
1987, Sankyo and Merck

Sales
Global sales of cholesterol- and triglyceride-lowering agents reached $30 billion in 2004.