Structural Biochemistry/Statin

Statin

Structure of simvastatin

Overview

Statins, also known as 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase (HMGCR) inhibitors, are a class of drugs that lower the level of cholesterol in the blood by reducing the production of cholesterol by the liver. Statins are inhibitors that block the enzyme HMGCR, which is responsible for the production of cholesterol. Because high cholesterol has been linked with the risk of heart disease, those with increased cholesterol levels may find statins useful as prevention. The top-selling statin is atorvastatin, with the trademark name Lipitor. Lipitor, which has been manufactured by Pfizer, has been useful in the stabilization of plaques and in preventing strokes.

History

In 1971, Akira Endo, got into research to search for inhibitors of HMGCR to lower the cholesterol levels in liver. He and his team argued that there are microorganisms that may produce this inhibitor of the enzymes to defend themselves against other organisms. The first isolated agent was mevastatin, a molecule created from the fungus “Penicillium citrinum”. By 1976, another statin, known as lovastatin, was isolated from the fungus “Aspergillus terreus”. A few years later, other isolated statins began to hit the market, including Pfizer’s Lipitor in 1985.

Then, a link between cholesterol and cardiovascular disease, called lipid hypothesis, had been suggested. Cholesterol is a waxy substance produced by the liver and found in certain foods, which is needed to make vitamin D and some hormones, create bile salts that assist people to digest fat and build cell walls. However, having too much cholesterol is not good since this can lead to heart attacks. During the Coronary Primary Prevention Trail of 1984, Daniel Steinberg, cholesterol researcher, conveyed that low-fat diet and poorly tolerated medicines such as cholestyramine, clofibrate, and nicotinic acid are all kinds of dietary measures for treatment. According to Steinberg, anything that will lower cholesterol can greatly reduce the risk of serious problems such as heart attacks and angina. However, many physicians including cardiologists remained unconvinced of Steinbergs theory.

To promote the use of statins, Merck convinced the public as well as doctors about the dangers of high blood cholesterol levels, and illustrated how statins were safe to take and would extend lives. Soon, people became familiar with their cholesterol numbers and understood the difference between what is good and what is bad cholesterol. With this happening, rival pharmaceutical companies started producing their own statins, such as pravastatin (Pravachol) that was manufactured by Sankyo and Bristol-Myers Squibb. In the year 1994, the results of a Merck-sponsored study, the Scandinavian Simvastatin Survival Study, or also known as "4S", were announced. Later Merck started selling simvastatin (Zocor), which was used by 4,444 patients with heart disease and high cholesterol. In just five years, the study concluded that many patients saw a 35% reduction in their cholesterol levels and the chance of them dying from heart attack were reduced by 42%. In the year 1955, Merck made over one billion US dollars profit with Zocor and Mevacor. In 2006, Endo was awarded the Japan Prize and the Lasker-DeBakey Clinical Medical Research Award in the year 2008.

Who Should Take It?

Statins are used for preventing and treating atherosclerosis, which causes chest pain, heart attack, stroke, and related deaths. So, people with abnormally elevated cholesterol levels or a history of heart attacks should consider taking statins. However, exercise and change in diet might be the first strategy to reduce cholesterol, before statin treatment is started.

Examples of Statin

Atovastatin (Lipitor, Torvast)
Fluvastatin (Lescol, Lescol XL)
Pravastatin (Pravachol, Selektine, Lipostat)
Rosuvastatin (Crestor)
Simvastatin (Zocor, Lipex)
Pitavastatin (Livalo, Pitava)
Cerivastatin (Lipobay, Baycol)
Lovastatin (Mevacor, Altocor, Altoprev)
Mevastatin (Compactin)
Simvastatin+Ezetimide (Vytorin)
Lovastatin+Niacin (Advicor)
Simvastatin+Niacin (Simcor)
Atorvastatin+Amlodipine (Caduet)

Mechanism

Statins all act by inhibiting HMGCR, which catalyzes the conversion of HMG-CoA to mevalonate during cholesterol synthesis. Individual statins are differently potent in reducing cholesterol (atorvastatin (Lipitor) and rosuvastatin (Crestor) are the most potent statins, while fluvastatin (Lescol) is the least potent statin currently on the market.

Structure of Cholesterol

Side Effects

Common side effects include: headache, nausea, vomiting, constipation, rash, diarrhea, muscle weakness and muscle pain. In very rare cases, serious and potentially fatal side effects such as liver failure and rhabdomyolysis (muscle degeneration) have occurred. Such side effects might be linked to interactions with other medications that increase the bioavailability of statins. Statins are known to increase the risk to develop type 2 diabetes, and are further discussed to affect cognitive function. On the one hand, statins might lead to working memory impairment, on the other hand, statins might reduce the risk to develop dementias such as Alzheimer disease.