Lovastatin, the first statin to be marketed

The statins form a class of hypolipidemic agents. They are used as pharmaceuticals to lower cholesterol levels in patients at risk for cardiovascular disease because of hypercholesterolemia.

Members

The statins are (brand names in countries other than the US can be different):

• atorvastatin (Lipitor®)
• fluvastatin (Lescol®)
• lovastatin (Mevacor®, Altocor®, not marketed in the UK)
• pravastatin (Pravachol®, Selektine®, Lipostat®)
• rosuvastatin (Crestor®)
• simvastatin (Zocor®)
• cerivastatin (Lipobay®, Baycol®) - marketing discontinued in 2001 by the manufacturer (Bayer) due to serious side-effects, especially when used in combination with fibrates.

Uses

Statins are the most potent cholesterol-lowering agents, lowering LDL-cholesterol (so-called "bad cholesterol") by 30–50%. However, they are less effective than the fibrates in reducing triglycerides and raising HDL-cholesterol ("good cholesterol"). As up to 50% of all circulating cholesterol originates in the diet, statins are theoretically only prescribed after dietary intervention has not had the desired effect. In practice, the yield of dieting is small, and many doctors omit this step altogether.

The statins play an important role in primary and secondary prevention of coronary heart disease and myocardial infarction. There is ongoing research into other areas where statins appear to have an effect: inflammation, dementia, and neoplasm (tumors).

Pharmacology

Groups

There are two groups of statins:

• Fermentation-derived: lovastatin, simvastatin and pravastatin
• Synthetic: fluvastatin, atorvastatin, cerivastatin and rosuvastatin

Of the groups, the former appears to be more effective in reducing LDL, but there is no clear explanation behind this phenomenon.

Mode of action

The HMG-CoA reductase pathway

Statins act by competitively inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, an enzyme of the HMG-CoA reductase pathway, the body's metabolic pathway for the synthesis of cholesterol.

Although statins inhibit endogenous cholesterol synthesis, their action goes further than that. By reducing intracellular cholesterol levels, liver cells upregulate expression of the LDL receptor, leading to increased clearance of Low-Density Lipoprotein from the bloodstream. This mechanism was clarified by Dr Michael S. Brown and Dr Joseph L. Goldstein, who received the Nobel Prize in Physiology or Medicine for their work in 1985.

Non-cholesterol related actions

Statins exhibit action beyond lipid-lowering activity in the prevention of atherosclerosis. There are four proposed mechanisms by which statins are thought to prevent cardiovascular disease (all are the subject of a large body of biomedical research):

1. Improving endothelial function
2. Modulate inflammatory responses
3. Maintain plaque stability
4. Prevent thrombus formation

Safety

While many patients develop muscle cramps and gastrointestinal upset on statin therapy, these usually resolve on temporarily lowering the dose. Liver enzyme derangements may occur, which generally return to normal after briefly discontinuing the drug. Some report headaches. Other side-effects are rare.

A main safety concern is rhabdomyolysis, the pathological breakdown of skeletal muscle leading to acute renal failure when muscle breakdown products damage the kidney. A 2004 study (Graham et al) found that if 10,000 patients are treated for one year, 0.44 of those will develop this side-effect. This is similar for all commonly used statins. Cerivastatin, which was withdrawn in 2001, had a much higher incidence (more than 10x higher). Combining any statin with a fibrate, another category of lipid-lowering drugs, increased the risks for rhabdomyolysis to almost 6.0 per 10,000 person-years.

Routine monitoring of liver enzymes and creatine kinase has now been abandoned by most physicians, although this is still considered prudent in those on high-dose statins or those on statin/fibrate combinations, and mandatory in muscle cramps or deterioration in renal function.

History

Research into inhibitors of HMG-CoA reductase were commenced in 1971 by Dr Akira Endo and Dr Masao Kuroda of Tokyo, Japan (Endo 1992). This team reasoned that certain microorganisms may produce inhibitors of the enzyme to defend themselves against other organisms, as mevalonate is a precursor of many substances required by organisms for the maintenance of their cell wall (ergosterol) or cytoskeleton (isoprenoids).

The first agent to be isolated was mevastatin (ML-236B), a molecule produced by Penicillium citrinum . The pharmaceutical company Merck & Co. showed an interest in the Japanese research in 1976, and isolated lovastatin (mevinolin, MK803), the first statin to be commercially marketed, from the mold Aspergillus terreus .

See also

• Scandinavian Simvastatin Survival Study (4S)
• Heart protection study (HPS)

References

• Endo A. The discovery and development of HMG-CoA reductase inhibitors. J Lipid Res 1992;33:1569-82. PMID 1464741.
• Furberg CD. Natural statins and stroke risk. Circulation 1999;99:185-188. PMID 9892578.
• Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L, Gurwitz JH, Chan KA, Goodman MJ, Platt R. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004;292:2585-90. PMID 15572716.