Chemistry:Simvastatin

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Short description: Lipid-lowering medication
Simvastatin
Simvastatin.svg
Simvastatin3Dan.gif
Clinical data
Pronunciation/ˈsɪmvəstætɪn/
Trade namesZocor, other
AHFS/Drugs.comMonograph
MedlinePlusa692030
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability5%
Protein binding95%
MetabolismLiver (CYP3A4)
Elimination half-life2 hours for simvastatin and 1.9 hours for simvastatin acid
ExcretionKidney 13%, faecal 60%
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC25H38O5
Molar mass418.574 g·mol−1
3D model (JSmol)
  (verify)

Simvastatin, sold under the brand name Zocor among others, is a statin, a type of lipid-lowering medication.[3] It is used along with exercise, diet, and weight loss to decrease elevated lipid levels.[3] It is also used to decrease the risk of heart problems in those at high risk.[3] It is taken by mouth.[3]

Common side effects include constipation, headaches, and nausea.[3] Serious side effects may include muscle breakdown, liver problems, and increased blood sugar levels.[3] A lower dose may be needed in people with kidney problems.[3] There is evidence of harm to the developing baby when taken during pregnancy[3][4] and it should not be used by those who are breastfeeding.[3] It is in the statin class of medications and works by decreasing the manufacture of cholesterol by the liver.[3]

Simvastatin is made from the fungus Aspergillus terreus.[5] It was patented by Merck in 1980, and came into medical use in 1992.[5][6] Simvastatin is available as a generic medication,[3] and is on the World Health Organization's List of Essential Medicines.[7] In 2021, it was the sixteenth most commonly prescribed medication in the United States, with more than 30 million prescriptions.[8][9]

Medical uses

The primary uses of simvastatin are to treat dyslipidemia and to prevent atherosclerosis-related complications such as stroke and heart attacks in those who are at high risk.[3] It is recommended to be used as an addition to a low-cholesterol diet.[3]

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.[10]

The Heart 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.[11]

Statins in general have been proposed as beneficial in reducing the progression of Age-related Macular Degeneration (AMD).[12] Multiple observational studies have been conducted[13][14] 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.

Contraindications

Simvastatin is contraindicated with pregnancy, breastfeeding, and liver disease.[15] 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.[16] High doses of simvastatin are also contraindicated with the widely used antihypertensive amlodipine.[17] A lower dose is also recommended in people taking the calcium channel blockers, verapamil and diltiazem, as well as those taking amiodarone.[18][19]

Adverse effects

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.[11] Cholestatic hepatitis, hepatic cirrhosis, rhabdomyolysis (destruction of muscles and blockade of renal system), and myositis have been reported in patients receiving the drug chronically.[20] Serious allergic reactions to simvastatin are rare.[15]

A type of DNA variant known as a single nucleotide polymorphism (SNP) may help predict individuals prone to developing myopathy when taking simvastatin; a study ultimately including 32,000 patients concluded the carriers of one or two risk alleles of a particular SNP, rs4149056,[21] were at a five-fold or 16-fold increased risk, respectively.[22] In 2012, the Clinical Pharmacogenetics Implementation Consortium has released guidelines regarding the use of rs4149056 genotype in guiding dosing of simvastatin[23] and updated the guideline in 2014.[24]

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 of type 2 diabetes, and muscle injury.[25] The new guidance indicates:

  • FDA has found that liver injury associated with statin use is rare but can occur.
  • The reports about memory loss, forgetfulness, and confusion span all statin products and all age groups. The FDA says these experiences are rare, but that those affected often report feeling "fuzzy" or unfocused in their thinking.
  • A small increased risk of raised blood sugar levels and the development of type 2 diabetes have been reported with the use of statins. A 2010 published meta-analysis found for every 255 patients taking a statin for 4 years, one additional case of diabetes would occur whilst preventing 5.4 major coronary events.[26]
  • Some drugs interact with statins in a way that increases the risk of muscle injury called myopathy, characterized by unexplained muscle weakness or pain.

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.[27] 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.[28] 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."[17]

Interactions

Simvastatin has important interactions with grapefruit 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 of rhabdomyolysis.[17]

Consuming large amounts of grapefruit juice increases serum levels of simvastatin by up to three-fold, increasing the risk of side effects.[29][30][31][32] The FDA recommends that people taking statins should avoid consuming more than a quart (946 ml) of grapefruit juice per day.[17]

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 drugs fluconazole, itraconazole, or posaconazole; the antibiotics erythromycin, clarithromycin, or telithromycin; HIV protease inhibitors; the antidepressant nefazodone; the cardiovascular drug gemfibrozil; the immunosuppressant ciclosporin, or the endometriosis drug danazol. Reduced maximum doses of simvastatin apply for patients taking certain other drugs, including the cardiovascular drugs verapamil, diltiazem, amiodarone, amlodipine, and ranolazine.[17][33]

Pharmacology

Main page: Biology:Statin

Pharmacodynamics

All statins act by inhibiting 3-hydroxy-3-methylglutaryl (HMG) coenzyme A reductase. HMG-CoA reductase, the rate-limiting enzyme of the HMG-CoA reductase pathway, the metabolic pathway responsible for the endogenous production of cholesterol. Statins are more effective than other lipid-regulating drugs at lowering LDL-cholesterol concentration, but they are less effective than the fibrates 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).[34]

Simvastatin is an effective serum lipid-lowering drug that can decrease low density lipoprotein (LDL) levels by up to 50%.[citation needed] Simvastatin had been shown to interact with lipid-lowering transcription factor PPAR-alpha[35] and that interaction might control the neurotrophic action of the drug.

Pharmacokinetics

The drug is in the form of an inactive lactone that is hydrolyzed after ingestion to produce the active β-hydroxyacid form. Simvastatin is primarily metabolized by CYP3A4 yielding products which are also active HMG-CoA reductase inhibitors.[1]

History

The development of simvastatin was closely linked with lovastatin. Biochemist Jesse Huff and his colleagues at Merck began researching the biosynthesis of cholesterol in the early 1950s.[36] In 1956, mevalonic acid was isolated from a yeast extract by Karl Folkers, Carl Hoffman, and others at Merck, while Huff and his associates confirmed that mevalonic acid was an intermediate in cholesterol biosynthesis. In 1959, the HMG-CoA reductase enzyme (a major contributor of internal cholesterol production) was discovered by researchers at the Max Planck Institute. This discovery encouraged scientists worldwide to find an effective inhibitor of this enzyme.[37]

By 1976, Akira Endo had isolated the first inhibitor, mevastatin, from the fungus Penicillium citrinium while working at Daiichi Sankyo in Japan.[38] In 1979, Hoffman and colleagues isolated lovastatin from a strain of the fungus Aspergillus terreus. While developing and researching lovastatin, Merck scientists synthetically derived a more potent HMG-CoA reductase inhibitor from a fermentation product of A. terreus, which was designated MK-733 (later to be named simvastatin).[39]

In 1994, publication of the results of the Scandinavian 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.[40][41]

Society and culture

Economics

Prior to losing US patent protection, simvastatin was Merck & Co.'s largest-selling drug.[42]

Under provisions of the Patient 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 on United States Preventive Services Task Force (USPSTF) recommendations.[43][44][45]

Zocor had an original patent expiry date in December 2005, but was extended by the United States Patent and Trademark Office (USPTO) to expire in June 2006.[46]

Brand names

Simvastatin was initially marketed by Merck & Co under the brand name Zocor but is available generically in most countries following the patent expiry.[citation needed] A combination of simvastatin along with ezetimibe is sold under the brand name Vytorin and is jointly marketed by Merck and Schering-Plough.[citation needed]

Brand names include Zocor, Zocor Heart Pro, marketed by the pharmaceutical 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]

The US patent for Zocor expired in June 2006.[42]

References

  1. ↑ 1.0 1.1 "Zocor- simvastatin tablet, film coated". 9 August 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8f55d5de-5a4f-4a39-8c84-c53976dd6af9. 
  2. ↑ "Active substance: simvastatin". List of nationally authorised medicinal products. European Medicines Agency. 26 November 2020. https://www.ema.europa.eu/documents/psusa/simvastatin-list-nationally-authorised-medicinal-products-psusa/00002709/202004_en.pdf. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 "Simvastatin". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/simvastatin.html. 
  4. ↑ "Prescribing medicines in pregnancy database". Australian Government. 3 March 2014. http://www.tga.gov.au/hp/medicines-pregnancy.htm#.U1Yw8Bc3tqw. 
  5. ↑ 5.0 5.1 Plant bioactives and drug discovery : principles, practice, and perspectives. Hoboken, N.J.: John Wiley & Sons. 2012. p. 104. ISBN 9780470582268. https://books.google.com/books?id=hhraBwhymOUC&pg=PA104. 
  6. ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 472. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA472. 
  7. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  8. ↑ "The Top 300 of 2021". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  9. ↑ "Simvastatin - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Simvastatin. 
  10. ↑ "Simvastatin: a review". Expert Opinion on Pharmacotherapy 5 (12): 2583–96. December 2004. doi:10.1517/14656566.5.12.2583. PMID 15571475. 
  11. ↑ 11.0 11.1 "Zocor Full Prescribing Information". U.S. Food and Drug Administration (FDA). http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019766s093lbl.pdf. 
  12. ↑ "The Question of a Role for Statins in Age-Related Macular Degeneration". International Journal of Molecular Sciences 19 (11): 3688. November 2018. doi:10.3390/ijms19113688. PMID 30469381. 
  13. ↑ "The Association of Statin Use with Age-Related Macular Degeneration Progression: The Age-Related Eye Disease Study 2 Report Number 9". Ophthalmology 122 (12): 2490–6. December 2015. doi:10.1016/j.ophtha.2015.08.028. PMID 26435335. 
  14. ↑ "Age-related macular degeneration and protective effect of HMG Co-A reductase inhibitors (statins): results from the National Health and Nutrition Examination Survey 2005-2008". Eye 28 (4): 472–80. April 2014. doi:10.1038/eye.2014.8. PMID 24503725. 
  15. ↑ 15.0 15.1 "Zocor". RxList. 14 November 2012. http://www.rxlist.com/zocor-drug/consumer-side-effects-precautions.htm. 
  16. ↑ "Simvastatin". LactMed. U.S. National Library of Medicine. http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~5v9vCs:1. 
  17. ↑ 17.0 17.1 17.2 17.3 17.4 "FDA Drug Safety Communication: New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury". U.S. Food and Drug Administration (FDA). 8 June 2011. https://www.fda.gov/Drugs/DrugSafety/ucm256581.htm. 
  18. ↑ "Simvastatin: updated advice on drug interactions - updated contraindications". Drug Safety Update (Government of the United Kingdom) 6 (1): S1. August 2012. https://www.gov.uk/drug-safety-update/simvastatin-updated-advice-on-drug-interactions. Retrieved 3 November 2015. 
  19. ↑ "FDA Drug Safety Communication: Revised dose limitation for Zocor (simvastatin) when taken with amiodarone". 15 December 2011. https://www.fda.gov/Drugs/DrugSafety/ucm283137.htm. 
  20. ↑ Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. 2008. pp. 1431–3. 
  21. ↑ rs4149056
  22. ↑ "SLCO1B1 variants and statin-induced myopathy--a genomewide study". The New England Journal of Medicine 359 (8): 789–99. August 2008. doi:10.1056/NEJMoa0801936. PMID 18650507. 
  23. ↑ "The clinical pharmacogenetics implementation consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update". Clinical Pharmacology and Therapeutics 96 (4): 423–8. October 2014. doi:10.1038/clpt.2014.125. PMID 24918167. 
  24. ↑ "The clinical pharmacogenomics implementation consortium: CPIC guideline for SLCO1B1 and simvastatin-induced myopathy". Clinical Pharmacology and Therapeutics 92 (1): 112–7. July 2012. doi:10.1038/clpt.2012.57. PMID 22617227. 
  25. ↑ "FDA Expands Advice on Statin Risks". U.S. Food and Drug Administration (FDA). https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm293330.htm. 
  26. ↑ "Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials" (in English). Lancet 375 (9716): 735–42. February 2010. doi:10.1016/S0140-6736(09)61965-6. PMID 20167359. 
  27. ↑ "FDA Drug Safety Communication: Ongoing safety review of high-dose Zocor (simvastatin) and increased risk of muscle injury". U.S. Food and Drug Administration (FDA). 19 March 2010. https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm204882.htm. 
  28. ↑ "Simvastatin can damage muscles in high doses". USA Today. 9 June 2011. http://yourlife.usatoday.com/health/medical/story/2011/06/Simvastatin-can-damage-muscles-in-high-doses/48208588/1. "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." 
  29. ↑ "Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors". Clinical Pharmacology and Therapeutics 64 (5): 477–83. November 1998. doi:10.1016/S0009-9236(98)90130-8. PMID 9834039. 
  30. ↑ "Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin". British Journal of Clinical Pharmacology 58 (1): 56–60. July 2004. doi:10.1111/j.1365-2125.2004.02095.x. PMID 15206993. 
  31. ↑ "Cholesterol-lowering medicines, statins - Interactions". NHS. 16 April 2012. http://www.nhs.uk/conditions/cholesterol-lowering-medicines-statins/pages/interactions---other-medicines.aspx. 
  32. ↑ "Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin". Clinical Pharmacology and Therapeutics 68 (4): 384–90. October 2000. doi:10.1067/mcp.2000.110216. PMID 11061578. 
  33. ↑ "Information on Simvastatin/Amiodarone". U.S. Food and Drug Administration (FDA). 8 August 2008. https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm118869.htm. 
  34. ↑ "Pleiotropic effects of statins: evidence against benefits beyond LDL-cholesterol lowering". American Journal of Cardiovascular Drugs 10 (Suppl 1): 10–7. 2010. doi:10.2165/1158822-S0-000000000-00000. PMID 21391729. 
  35. ↑ "HMG-CoA Reductase Inhibitors Bind to PPARα to Upregulate Neurotrophin Expression in the Brain and Improve Memory in Mice". Cell Metabolism 22 (2): 253–65. August 2015. doi:10.1016/j.cmet.2015.05.022. PMID 26118928. 
  36. ↑ Triumph of the Heart: The Story of Statins. Oxford University Press. 2009. pp. 59. ISBN 978-0198043515. 
  37. ↑ Endo, Akira (2010). "A historical perspective on the discovery of statins" (in en). Proceedings of the Japan Academy, Series B 86 (5): 484–493. doi:10.2183/pjab.86.484. ISSN 0386-2208. PMID 20467214. PMC 3108295. Bibcode: 2010PJAB...86..484E. http://www.jstage.jst.go.jp/article/pjab/86/5/86_5_484/_article. 
  38. ↑ "Pleiotropic effects of statins". Annual Review of Pharmacology and Toxicology 45: 89–118. 2005. doi:10.1146/annurev.pharmtox.45.120403.095748. PMID 15822172. 
  39. ↑ Allan Afuah, ed (1998). "Case 10: Merck(A): Mevacor". Innovation Management - Strategies, Implementation, and Profits. Oxford University Press. ISBN 978-0-19-511346-4. http://www-personal.umich.edu/~afuah/cases/case10.html. Retrieved 19 July 2006. 
  40. ↑ "Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors". Nature Reviews. Drug Discovery 2 (7): 517–26. July 2003. doi:10.1038/nrd1112. PMID 12815379. 
  41. ↑ "Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)". Lancet 344 (8934): 1383–9. November 1994. doi:10.1016/S0140-6736(94)90566-5. PMID 7968073. 
  42. ↑ 42.0 42.1 "Merck Loses Protection for Patent on Zocor". The New York Times. 23 June 2006. https://www.nytimes.com/2006/06/23/business/23statin.html. 
  43. ↑ "PPACA no cost-share preventive medications". Cigna. https://www.cigna.com/assets/docs/about-cigna/no-cost-share-preventive-medications.pdf. 
  44. ↑ "Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: Recommendation Statement". American Family Physician 95 (2). 15 January 2017. https://www.aafp.org/afp/2017/0115/od1.html. Retrieved 31 March 2020. 
  45. ↑ "Recommendation: Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: Preventive Medication". 15 November 2016. https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/statin-use-in-adults-preventive-medication. 
  46. ↑ "Merck gets Zocor patent extension". 3 November 2002. https://www.thepharmaletter.com/article/merck-gets-zocor-patent-extension. 



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