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.
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.
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.
The statins include, in alphabetical order (brand names vary in different countries):
| Statin | Brand name | Derivation |
| Atorvastatin | Lipitor, Torvast | Synthetic |
| Cerivastatin | Lipobay, Baycol. (Withdrawn from the market in August, 2001 due to risk of serious Rhabdomyolysis | Synthetic |
| Fluvastatin | Lescol, Lescol XL | Synthetic |
| Lovastatin | Mevacor, Altocor, Altoprev | Fermentation-derived |
| Mevastatin | - | Naturally-occurring compound. Found in red yeast rice. |
| Pitavastatin | Livalo, Pitava | Synthetic |
| Pravastatin | Pravachol, Selektine, Lipostat | Fermentation-derived |
| Rosuvastatin | Crestor | Synthetic |
| Simvastatin | Zocor, Lipex | Fermentation-derived. (Simvastatin is a synthetic derivate of a fermentation product) |
| Simvastatin+Ezetimibe | Vytorin | Combination therapy |
| Lovastatin+Niacin extended-release | Advicor | Combination therapy |
| Atorvastatin+Amlodipine Besylate | Caduet | Combination therapy - Cholesterol+Blood Pressure |
| Simvastatin+Niacin extended-release | Simcor | Combination therapy |
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. The relative potency of pitavastatin has not yet been fully established.
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 increae 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 investigation.
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 (however it is a major inhibitor of only lovastatin, simvastatin and to a lesser degree atorvastatin) and some other medications (it had been thought that flavonoids were responsible). This increases the levels 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. This is not recommended as a result of the increased risk and potential for statin toxicity.
Most circulating cholesterol is manufactured internally, in amounts of about 1000 mg/day, via steroid biosynthesis through the HMG-CoA reductase pathway. Cholesterol, both from dietary intake and secreted into the duodenum as bile from the liver, is typically absorbed at a rate of 50% by the small intestines. The typical diet in the United States and many other Western countries is estimated as adding about 200–300 mg/day to intestinal intake, an amount much smaller than that secreted into the intestine in the bile. Thus internal production is an important factor.
Cholesterol is not water-soluble, and is therefore carried in the blood in the form of lipoproteins, the type being determined by the apoprotein, a protein coating that acts as an emulsifier. The relative balance between these lipoproteins is determined by various factors, including genetics, diet, and insulin resistance. Low density lipoprotein (LDL) and very low density lipoprotein (VLDL) carry cholesterol toward tissues, and elevated levels of these lipoproteins are associated with atheroma formation (fat-containing deposits in the arterial wall) and cardiovascular disease. Conversely, High density lipoprotein (HDL), carries cholesterol back to the liver and is associated with protection against cardiovascular disease.
Statins act by competitively inhibiting HMG-CoA reductase, the first committed enzyme of the HMG-CoA reductase pathway. By reducing intracellular cholesterol levels, they cause liver cells to make more LDL receptors, leading to increased clearance of low-density lipoprotein from the bloodstream.
Direct evidence of the action of statin-based cholesterol lowering on atherosclerosis was presented in the ASTEROID trial, which demonstrated regression of atheroma employing intravascular ultrasound.
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