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The statins (or HMG-CoA reductase inhibitors ) form a class of hypolipidemic drugs used to lower cholesterol levels in people with or at risk of cardiovascular disease. They lower cholesterol by inhibiting the enzyme HMG-CoA reductase, which is the rate-limiting enzyme of the mevalonate pathway of cholesterol synthesis. Inhibition of this enzyme in the liver stimulates LDL receptors, resulting in an increased clearance of low-density lipoprotein (LDL) from the bloodstream and a decrease in blood cholesterol levels. The first results can be seen after one week of use and the effect is maximal after four to six weeks.
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 . Dr Endo was awarded the 2006 Japan Prize for his work on the development of statins, and the Clinical Medical Research Award from the Lasker Foundation in 2008.
Mechanism of action
Statins act by inhibiting the enzyme HMG-CoA reductase, the enzyme controlling the first committed step of sterol (cholesterol) synthesis, in the liver. Because statins are similar to HMG-CoA on a molecular level they take the place of HMG-CoA in the enzyme and reduce the rate by which it is able to produce mevalonate, the next molecule in the cascade that eventually produces cholesterol, as well as a number of other compounds.
Inside the liver cell, other enzymes of the protease class sense the decreased level of cholesterol produced. In response, they cleave a protein called "membrane-bound sterol regulatory element binding protein", which then responds by migrating to the nucleus to increase production of various other proteins and enzymes, including the LDL receptor. The LDL receptor then relocates to the cell membrane of the liver cell, and binds to passing low density lipoprotein and very low density lipoprotein particles (both containing cholesterol in the undesired form). LDL and VLDL enter the liver and are digested.
Indications and uses
Statins, the most potent cholesterol-lowering agents available, lower LDL cholesterol (so-called "bad cholesterol") by 1.8 mmol/l. This translates in a 60% decrease in the number of cardiac events (heart attack, sudden cardiac death), and a 17% reduced risk of stroke. They have less effect than the fibrates or niacin in reducing triglycerides and raising HDL-cholesterol ("good cholesterol"). Professional guidelines generally require that the patient has tried a cholesterol-lowering diet before statin use is considered; statins or other pharmacologic agents may then be recommended for patients who do not meet their lipid-lowering goals through diet and lifestyle approaches.
The indications for the prescription of statins have broadened over the years. Initial studies, such as the Scandinavian Simvastatin Survival Study (4S), supported the use of statins in secondary prevention for cardiovascular disease, or as primary prevention only when the risk for cardiovascular disease was significantly raised (as indicated by the Framingham risk score). Indications were broadened considerably by studies such as the Heart Protection Study (HPS), which showed preventative effects of statin use in specific risk groups, such as diabetics. The ASTEROID trial, published in 2006, using only a statin at high dose, achieved lower than usual target calculated LDL values and showed disease regression within the coronary arteries using intravascular ultrasonography.
Based on clinical trials, the National Cholesterol Education Program guidelines, and the increasing focus on aggressively lowering LDL-cholesterol, the statins continue to play an important role in both the primary and secondary prevention of coronary heart disease, myocardial infarction, stroke and peripheral artery disease.
Research continues into other areas where statins also appear to have a favorable effect: inflammation, dementia, cancer, nuclear cataracts, and hypertension.
Members
Fermentation-derived and synthetic
The statins are divided into two groups: fermentation-derived and synthetic.
The statins include, in alphabetical order (brand names vary in different countries):
LDL-lowering potency varies between agents. Cerivastatin is the most potent, followed by (in order of decreasing potency) atorvastatin, rosuvastatin, , simvastatin, lovastatin, pravastatin, and fluvastatin. The relative potency of pitavastatin has not yet been fully established.
Comparative effectiveness
No large scale comparison exists that examines the relative effectiveness of the various statins against one another for preventing hard cardiovascular outcomes, such as death or myocardial infarction.
An independent analysis has been done to compare atorvastatin, pravastatin and simvastatin, based on their effectiveness against placebos. It found that, at commonly prescribed doses, there are no statistically significant differences in reducing cardiovascular morbidity and mortality. The CURVES study, which compared the efficacy of different doses of atorvastatin, simvastatin, pravastatin, lovastatin, and fluvastatin for reducing LDL and total cholesterol in patients with hypercholesterolemia, found that atorvastatin was more effective without increasing adverse events.
Cost effectiveness
Statins vary in cost from $32 to $150 a month. Ninety days of generic simvastatin (40mg) from WalMart cost $10.00 on January 6, 2009. Consumer Reports recommends generic lovastatin, pravastatin, and simvastatin as cost-efficient "Best Buy" alternatives to more expensive branded drugs, for those in whom it is suitable. Costs can be further reduced by splitting pills in half.
Safety
Adverse effects
Statins are generally well-tolerated and have only two major side effects that occur relatively rarely: raised liver enzymes and skeletal muscle damage.
While some patients on statin therapy report myalgias, muscle cramps, or far less-frequent gastrointestinal or other symptoms, 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. Coenzyme Q10 (ubiquinone) levels are decreased in statin use; Q10 supplements are sometimes used to treat statin-associated myopathy, though evidence of their effectiveness is currently lacking. A common variation in the SLCO1B1 gene, which participates in the absorption of statins, has been shown to significantly increase the risk of myopathy.
One 2004 study found that of 10,000 patients treated for one year, 0.44 will develop rhabdomyolysis. 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-lives and more cellular specificity, have had a better ratio of efficacy to lower adverse effect rates. The risk of myopathy is lowest with pravastatin and fluvastatin probably because they are more hydrophillic and as a result have less muscle penetration. Lovastatin induces the expression of gene atrogin-1, which is believed to be responsible in promoting muscle fiber damage.
Despite initial concerns that statins might increase the risk of cancer, various studies concluded later that statins have no influence on cancer risk (including the heart protection study and a 2006 meta-analysis). Indeed, a 2005 trial showed that patients taking statins for over 5 years reduced their risk of colorectal cancer by 50%; this effect was not exhibited by fibrates. The trialists warn that the number needed to treat would approximate 5000, making statins unlikely tools for primary prevention. However, in a recent meta-analysis of 23 statin treatment arms with 309,506 person-years of follow-up, there was an inverse relationship between achieved LDL-cholesterol levels and rates of newly diagnosed cancer that the authors claim requires further invest