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| Pronunciation | /ˈsɪmvəstætɪn/ |
| Trade names | Zocor, other |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a692030 |
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| Routes of administration | By mouth |
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| Bioavailability | 5% |
| Protein binding | 95% |
| Metabolism | Liver (CYP3A4) |
| Eliminationhalf-life | 2 hours for simvastatin and 1.9 hours for simvastatin acid |
| Excretion | Kidney 13%,faecal 60% |
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| ECHA InfoCard | 100.115.749 |
| Chemical and physical data | |
| Formula | C25H38O5 |
| Molar mass | 418.574 g·mol−1 |
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Simvastatin, sold under the brand nameZocor among others, is astatin, a type oflipid-lowering medication.[4] It is used along with exercise, diet, and weight loss to decreaseelevated lipid levels.[4] It is also used to decrease the risk ofheart problems in those at high risk.[4] It is taken by mouth.[4]
Common side effects include constipation, headaches, and nausea.[4] Serious side effects may includemuscle breakdown, liver problems, and increased blood sugar levels.[4] A lower dose may be needed in people withkidney problems.[4] There is evidence of harm to the developing baby when taken duringpregnancy[4][5] and it should not be used by those who arebreastfeeding.[4] It is in thestatin class of medications and works by decreasing the manufacture of cholesterol by the liver.[4]
Simvastatin is made from the fungusAspergillus terreus.[6] It was patented byMerck in 1980, and came into medical use in 1992.[6][7] Simvastatin is available as ageneric medication,[4] and is on theWorld Health Organization's List of Essential Medicines.[8] In 2022, it was the nineteenth most commonly prescribed medication in the United States, with more than 26 million prescriptions.[9][10]
The primary uses of simvastatin are to treatdyslipidemia and to prevent atherosclerosis-related complications such as stroke and heart attacks in those who are at high risk.[4] It is recommended to be used as an addition to a low-cholesterol diet.[4]
In heart protection studies, simvastatin showed the ability to lower LDL cholesterol by about 1·5 mmol/L, which resulted in substantial reductions in mortality rates. Simvastatin also reduced the numbers of other events like heart attacks, strokes, and revascularizations and MI significantly.[11]
TheHeart Protection Study evaluated the effects of simvastatin in people with risk factors including existing cardiovascular disease, diabetes, or stroke, but having relatively low LDL cholesterol. In this trial, which lasted 5.4 years, overall mortality was reduced by 13% and cardiovascular mortality was reduced by 18%. People receiving simvastatin experienced 38% fewer nonfatal heart attacks and 25% fewer strokes.[12]
Statins in general have been proposed as beneficial in reducing the progression of Age-related Macular Degeneration (AMD).[13] Multiple observational studies have been conducted[14][15] to analyse the benefits of statin use in delaying the progression of AMD but have resulted in conflicting outcomes. Given the current available information, simvastatin should not be recommended solely for the treatment of AMD.[citation needed]
Simvastatin iscontraindicated with pregnancy, breastfeeding, and liver disease.[16] Pregnancy must be avoided while on simvastatin due to potentially severe birth defects. Patients cannot breastfeed while on simvastatin due to potentially disrupting the infant's lipid metabolism.[17] High doses of simvastatin are also contraindicated with the widely used antihypertensiveamlodipine.[18] A lower dose is also recommended in people taking the calcium channel blockers,verapamil anddiltiazem, as well as those takingamiodarone.[19][20]
Common side effects (>1% incidence) may include indigestion and eczema. There is evidence to suggest that rare side effects such as joint pain, memory loss, and muscle cramps are more likely to occur in patients who take higher doses of simvastatin.[12] Cholestatic hepatitis, hepatic cirrhosis,rhabdomyolysis (destruction of muscles and blockade of renal system), and myositis have been reported in patients receiving the drug chronically.[21] Serious allergic reactions to simvastatin are rare.[16]
A type ofDNA variant known as asingle nucleotide polymorphism (SNP) may help predict individuals prone to developingmyopathy when taking simvastatin; a study ultimately including 32,000 patients concluded the carriers of one or two riskalleles of a particular SNP, rs4149056,[22] were at a five-fold or 16-fold increased risk, respectively.[23] In 2012, the Clinical Pharmacogenetics Implementation Consortium has released guidelines regarding the use of rs4149056 genotype in guiding dosing of simvastatin[24] and updated the guideline in 2014.[25]
In March 2012, the U.S.Food and Drug Administration (FDA) updated its guidance for statin users to address reports of memory loss, liver damage, increased blood sugar, development oftype 2 diabetes, and muscle injury.[26] The new guidance indicates:
On 19 March 2010, the FDA issued another statement regarding simvastatin, saying it increases the risk of muscle injury (myopathy) when taken at high doses or at lower doses in combination with other drugs.[28] The highest dose rate causes muscle damage in 610 of every 10,000 people in contrast to a lower dose, which causes muscle damage in eight of 10,000 people.[29] The FDA warning, released again on 8 June 2011, suggested that high-dose "simvastatin should be used only in patients who have been taking this dose for 12 months or more without evidence of muscle injury" and that it "should not be started in new patients, including patients already taking lower doses of the drug."[18]
Simvastatin has important interactions withgrapefruit juice and other drugs, including some that are commonly used for the treatment of cardiovascular disease. These interactions are clinically important because increasing simvastatin serum levels above those normally provided by the maximum recommended dose increases the risk of muscle damage, including the otherwise rare and potentially fatal side effect ofrhabdomyolysis.[18]
Consuming large amounts of grapefruit juice increases serum levels of simvastatin by up to three-fold, increasing the risk of side effects.[30][31][32][33] The FDA recommends that people taking statins should avoid consuming more than a quart (946 ml) of grapefruit juice per day.[18]
Simvastatin also interacts with other drugs, including some used to treat cardiovascular problems. It should not be taken by people who are also taking the antifungal drugsfluconazole,itraconazole, orposaconazole; the antibioticserythromycin,clarithromycin, ortelithromycin; HIV protease inhibitors; the antidepressantnefazodone; the cardiovascular druggemfibrozil; the immunosuppressantciclosporin, or the endometriosis drugdanazol. Reduced maximum doses of simvastatin apply for patients taking certain other drugs, including the cardiovascular drugsverapamil,diltiazem,amiodarone,amlodipine, andranolazine.[18][34]
All statins act by inhibiting 3-hydroxy-3-methylglutaryl (HMG) coenzyme A reductase.HMG-CoA reductase, therate-limitingenzyme of theHMG-CoA reductase pathway, themetabolic pathway responsible for the endogenous production ofcholesterol. Statins are more effective than other lipid-regulating drugs at loweringLDL-cholesterol concentration, but they are less effective than thefibrates in reducing triglyceride concentration. However, statins reduce cardiovascular disease events and total mortality irrespective of the initial cholesterol concentration. This is a major piece of evidence that statins work in another way than the lowering of cholesterol (called pleiotropic effects).[35]
Simvastatin is an effective serumlipid-lowering drug that can decreaselow density lipoprotein (LDL) levels by up to 50%.[citation needed] Simvastatin had been shown to interact with lipid-lowering transcription factor PPAR-alpha[36] and that interaction might control the neurotrophic action of the drug.
The drug is in the form of an inactivelactone that ishydrolyzed after ingestion to produce the active β-hydroxyacid form. Simvastatin is primarily metabolized byCYP3A4 yielding products which are also active HMG-CoA reductase inhibitors.[2]
The development of simvastatin was closely linked withlovastatin. Biochemist Jesse Huff and his colleagues at Merck began researching the biosynthesis of cholesterol in the early 1950s.[37] In 1956,mevalonic acid was isolated from a yeast extract byKarl Folkers, Carl Hoffman, and others at Merck, while Huff and his associates confirmed that mevalonic acid was an intermediate in cholesterol biosynthesis. In 1959, theHMG-CoA reductase enzyme (a major contributor of internal cholesterol production) was discovered by researchers at theMax Planck Institute. This discovery encouraged scientists worldwide to find an effective inhibitor of this enzyme.[38]
By 1976,Akira Endo had isolated the first inhibitor,mevastatin, from thefungusPenicillium citrinium while working atDaiichi Sankyo in Japan.[39] In 1979, Hoffman and colleagues isolated lovastatin from a strain of the fungusAspergillus terreus. While developing and researching lovastatin, Merck scientists synthetically derived a more potent HMG-CoA reductase inhibitor from a fermentation product ofA. terreus, which was designated MK-733 (later to be named simvastatin).[40]
In 1994, publication of the results of theScandinavian Simvastatin Survival Study (4S) provided the first unequivocal evidence that lowering LDL cholesterol via statin treatment reduces cardiovascular events and overall mortality. A total of 4,444 people with coronary heart disease and blood cholesterol levels from 5.5 to 8.0 mmol/L were randomized to simvastatin treatment or placebo and followed for an average of 5 years. Compared to the placebo group, those treated with simvastatin experienced a 30% decrease in overall mortality, a 42% reduction in coronary death, a 34% reduction in major coronary events, and a 37% reduction in revascularization procedures.[41][42]
Prior to losing US patent protection, simvastatin was Merck & Co.'s largest-selling drug.[43]
Under provisions of thePatient Protection and Affordable Care Act (PPACA) in the United States, health plans may cover the costs of simvastatin 10 mg, 20 mg, and 40 mg for adults aged 40–75 years based onUnited States Preventive Services Task Force (USPSTF) recommendations.[44][45][46]
Zocor had an original patent expiry date in December 2005, but was extended by theUnited States Patent and Trademark Office (USPTO) to expire in June 2006.[47]
Simvastatin was initially marketed byMerck & Co under the brand name Zocor but is available generically in most countries following the patent expiry.[citation needed] A combination of simvastatin along withezetimibe is sold under the brand nameVytorin and is jointly marketed by Merck andSchering-Plough.[citation needed]
Brand names include Zocor, Zocor Heart Pro, marketed by thepharmaceutical company Merck & Co., Simlup, Simvotin, Simcard (India), Denan (Germany), Liponorm, Sinvacor, Sivastin (Italy), Lipovas (Japan), Lodales (France), Zocord (Austria and Sweden), Zimstat, Simvahexal (Australia), Lipex (Australia and New Zealand), Simvastatin-Teva, Simvacor, Simvaxon, Simovil (Israel), available in Thailand under the brand Bestatin manufactured by Berlin Pharmaceutical Industry Co Ltd and others.[citation needed]
{{cite journal}}: CS1 maint: overridden setting (link){{cite journal}}: CS1 maint: overridden setting (link){{cite journal}}: CS1 maint: overridden setting (link){{cite journal}}: CS1 maint: overridden setting (link)The cholesterol-lowering drug simvastatin can cause severe muscle damage and should not be prescribed in high doses to patients who have taken it for less than a year or in any dose to people taking certain drugs, health officials said Tuesday. . . . Research has shown that the highest dose of simvastatin, 80 milligrams, causes muscle damage in 61 of every 1,000 patients, far higher than the eight-per-10,000 rate in patients taking a 40-milligram dose, Rosenblatt says.
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