Statin

The statins (or HMG-CoA reductase inhibitors) form a class of hypolipidemic agents, used as pharmaceuticals to lower cholesterol levels in people at risk for cardiovascular disease because of hypercholesterolemia.

Lovastatin, the first statin to be marketed

Members

The statins include, in alphabetical order (brand names vary in different countries):

• Atorvastatin (Lipitor)
• Cerivastatin (Lipobay, Baycol) – withdrawn from the market in 2001 due to risk of serious adverse effects.
• Fluvastatin (Lescol)
• Lovastatin (Mevacor, Altocor)
• Mevastatin – naturally-occurring compound, found in red yeast rice.
• Pravastatin (Pravachol, Selektine, Lipostat)
• Rosuvastatin (Crestor)
• Simvastatin (Zocor, Lipex)

LDL-lowering potency varies between agents. Cerivastatin is the most potent, followed by (in order of decreasing potency) rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, and fluvastatin.

Uses

Statins, the most potent cholesterol-lowering agents, lower LDL-cholesterol (so-called "bad cholesterol") by 30–55%. However, they have less effect than the fibrates or niacin in reducing triglycerides and raising HDL-cholesterol ("good cholesterol"). Statins and niacin combination, including at high dose have an excellent safety record. However, statins and fibrates, especially at higher doses have a track record and increased sides effects, such as myopathy, myositis and rhabdomyolysis and are therefore less frequently recommended, especially at high doses.

Most circulating cholesterol is manufactured internally, typically about 1000 mg/24 hours, out of other food chemistry. Cholesterol, both from dietary intake and secreted into the duodenum as bile from the liver, is typically about 50% absorbed by the small intestines. The typical diet in the United States, is estimated as adding about 200-300 mg/day to intestinal intake; much smaller than that secreted into the intestine in the bile. Thus internal production, and especially the circulating transport patterns of cholesterol within the carrying lipoprotein particles is the most important factor.

Because of the dominant role of internal production and multiple clinical trials checking effectiveness of various approaches to reduce cardiovascular events, physicians have increasingly prescribed statins as a more effective way to favorably alter lipoprotein traffic patterns within the blood stream. Low fat dietary intervention are rarely very effective; carbohydrate and hydrogenated fat reductions have generally been more effective, yet still far less effective than the statins. Indeed, because the diet recommendations often have so little effect, many doctors omit this step altogether. However, a recent statement by the American Heart Association advocated a combination of statins and omega-3 fatty acids found in fish oil

Based on clinical trials, the statins continue to play an important, indeed dominant and increasing role in both the primary (before any symptoms) and secondary (after onset of obvious clinical disease) prevention of coronary heart disease, myocardial infarction, stroke and peripheral artery disease. (A very short list of a few of the dozens of clinical research trials is noted below.)

Research continues into other areas where statins also appear to have a favorable effect: inflammation, dementia, and neoplastic conditions.

Pharmacology

Groups

Two groups of statins exist:

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

Fermentation-derived statins appear more effective in reducing LDL, but no clear explanation has accounted for this phenomenon.

Mode of action

The HMG-CoA reductase pathway

Statins act by competitively inhibiting 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, they cause liver cells to upregulate expression of the LDL receptor, leading to increased clearance of low-density lipoprotein from the bloodstream. Michael S. Brown and Joseph L. Goldstein received the Nobel Prize in Physiology or Medicine in 1985 for their work in clarifying this mechanism.

Non-cholesterol related actions

Statins exhibit action beyond lipid-lowering activity in the prevention of atherosclerosis. Researchers believe that statins prevent cardiovascular disease via four proposed mechanisms (all subjects of a large body of biomedical research):

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

Despite initial concerns that statins might increase the risk of cancer, various studies have confirmed that statins may reduce cancer risk by up to 50%. A large study compared 1953 patients with colorectal cancer and 2015 non-affected controls, and found that people taking statins for over 5 years had reduced their colorectal cancer risk by 50%. Fibrates had no effect. The trialists warn that the number needed to treat would approximate 5000, making statins unlikely tools for primary prevention.

In May 2005, results of an observational study of half a million U.S. veterans showed that people taking statins had a 50% reduced risk of developing any of several types of cancer. The authors state that this does not suggest that statins had a causal role in reducing cancer risk, as patients receiving statins possibly may also have benefited from unrelated health-related advice, such as stopping smoking.[1]

Pharmacogenomics

A 2004 study showed that patients with one of two common single nucleotide polymorphisms (small genetic variations) in the HMG-CoA reductase gene were less responsive to statins.

Safety

Adverse effects

While some patients report myalgias, muscle cramps far less frequently gastrointestinal or other symptoms on statin therapy, similar symptoms are also reported with placebo use in all the large statin safety/efficacy trials and usually resolve, either on their own or on temporarily lowering/stopping the dose. Liver enzyme derangements may also occur, typically in about 0.5%, are also seen at similar rates with placebo use and repeated enzyme testing, and generally return to normal either without discontinuance over time or after briefly discontinuing the drug. Multiple other side-effects occur rarely; typically also at similar rates with only placebo in the large statin safety/efficacy trials.

A clearer major safety concern, myositis, myopathy, rarely with rhabdomyolysis (the pathological breakdown of skeletal muscle) may lead to acute renal failure when muscle breakdown products damage the kidney. One 2004 study found that of 10,000 patients treated for one year, 0.44 will develop this side-effect. Cerivastatin, which was withdrawn by its manufacturer for this reason in 2001, had a much higher incidence (more than 10x). All commonly used statins show somewhat similar results, however the newer statins, characterized by longer pharmacological half-lifes and more cellular specificity, have had a better ratio of efficacy to lower adverse effect rates.

Drug interactions

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. Most physicians have now abandoned routine monitoring of liver enzymes and creatine kinase, although they still consider this prudent in those on high-dose statins or in those on statin/fibrate combinations, and mandatory in the case of muscle cramps or of deterioration in renal function.

Consumption of grapefruit or grapefruit juice inhibits the metabolism of statins—furanocoumarins in grapefruit juice inhibit the cytochrome P450 enzyme CYP3A4, which is involved in the metabolism of most statins and some other medications (it had been though that flavonoids were responsible). This increases the levels of of the statin, increasing the risk of dose-related adverse effects (including myopathy/rhabdomyolysis). Consequently, consumption of grapefruit juice is not recommended in patients undergoing therapy with most statins. An alternative, somewhat risky, approach is that some users take grapefruit juice to enhance the effect of lower (hence cheaper) doses of statins.

In one reported case a woman who had been taking simvastatin for 2 years was admitted to hospital with rhabdomyolysis: she had eaten one grapefruit a day for the two weeks prior to admission.

History

Akira Endo and Masao Kuroda of Tokyo, Japan commenced research into inhibitors of HMG-CoA reductase in 1971 (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 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 commercially marketed statin, from the mold Aspergillus terreus.

Specific trials

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