Editing Statin (section)

==Mechanism of action==
{{Main|Cholesterol#Homeostasis}}
[[File:Atorvastatin binding.png|thumb|Atorvastatin bound to HMG-CoA reductase: [[Protein Data Bank|PDB]] entry {{PDBe|1hwk}}<ref name="pmid11349148">{{cite journal | vauthors = Istvan ES, Deisenhofer J | title = Structural mechanism for statin inhibition of HMG-CoA reductase | journal = Science | volume = 292 | issue = 5519 | pages = 1160–1164 | date = May 2001 | pmid = 11349148 | doi = 10.1126/science.1059344 | s2cid = 37686043 | bibcode = 2001Sci...292.1160I }}</ref>]]
[[File:HMG-CoA reductase pathway.svg|thumb|546x546px|class=skin-invert-image|The HMG-CoA reductase pathway, which is blocked by statins via inhibiting the rate limiting enzyme [[HMG-CoA reductase]].]]

Statins act by [[competitive inhibitor|competitively inhibiting]] [[HMG-CoA reductase]], the rate-limiting [[enzyme]] of the [[mevalonate pathway]]. Because statins are similar in structure to [[HMG-CoA]] on a molecular level, they will fit into the enzyme's active site and compete with the native substrate (HMG-CoA). This competition reduces the rate by which [[HMG-CoA reductase]] is able to produce [[mevalonate]], the next molecule in the [[mevalonate pathway|cascade that eventually produces cholesterol]]. A variety of natural statins are produced by ''[[Penicillium]]'' and ''[[Aspergillus]]'' fungi as [[secondary metabolites]]. These natural statins probably function to inhibit HMG-CoA reductase enzymes in bacteria and fungi that compete with the producer.<ref name="Endo1992">{{cite journal | vauthors = Endo A | title = The discovery and development of HMG-CoA reductase inhibitors | journal = Journal of Lipid Research | volume = 33 | issue = 11 | pages = 1569–1582 | date = November 1992 | pmid = 1464741 | doi = 10.1016/S0022-2275(20)41379-3 | doi-access = free | title-link = doi }}</ref>

===Inhibiting cholesterol synthesis===
By inhibiting HMG-CoA reductase, statins block the pathway for synthesizing cholesterol in the liver. This is significant because most circulating cholesterol comes from internal manufacture rather than the diet. When the liver can no longer produce cholesterol, levels of cholesterol in the blood will fall. Cholesterol synthesis appears to occur mostly at night,<ref>{{cite journal | vauthors = Miettinen TA | title = Diurnal variation of cholesterol precursors squalene and methyl sterols in human plasma lipoproteins | journal = Journal of Lipid Research | volume = 23 | issue = 3 | pages = 466–473 | date = March 1982 | pmid = 7200504 | doi = 10.1016/S0022-2275(20)38144-X | doi-access = free | title-link = doi }}</ref> so statins with short [[half-life|half-lives]] are usually taken at night to maximize their effect. Studies have shown greater LDL and total cholesterol reductions in the short-acting [[simvastatin]] taken at night rather than the morning,<ref>{{cite journal | vauthors = Saito Y, Yoshida S, Nakaya N, Hata Y, Goto Y | title = Comparison between morning and evening doses of simvastatin in hyperlipidemic subjects. A double-blind comparative study | journal = Arteriosclerosis and Thrombosis | volume = 11 | issue = 4 | pages = 816–826 | date = July–August 1991 | pmid = 2065035 | doi = 10.1161/01.ATV.11.4.816 | doi-access = free | title-link = doi }}</ref><ref>{{cite journal | vauthors = Wallace A, Chinn D, Rubin G | title = Taking simvastatin in the morning compared with in the evening: randomised controlled trial | journal = BMJ | volume = 327 | issue = 7418 | pages = 788 | date = October 2003 | pmid = 14525878 | pmc = 214096 | doi = 10.1136/bmj.327.7418.788 }}</ref> but have shown no difference in the long-acting [[atorvastatin]].<ref>{{cite journal | vauthors = Cilla DD, Gibson DM, Whitfield LR, Sedman AJ | title = Pharmacodynamic effects and pharmacokinetics of atorvastatin after administration to normocholesterolemic subjects in the morning and evening | journal = Journal of Clinical Pharmacology | volume = 36 | issue = 7 | pages = 604–609 | date = July 1996 | pmid = 8844442 | doi = 10.1002/j.1552-4604.1996.tb04224.x | s2cid = 13586550 }}</ref>

===Increasing LDL uptake===
In rabbits, [[hepatocyte|liver cells]] sense the reduced levels of liver cholesterol and seek to compensate by synthesizing [[LDL receptor]]s to draw cholesterol out of the circulation.<ref name="Ma1986">{{cite journal | vauthors = Ma PT, Gil G, Südhof TC, Bilheimer DW, Goldstein JL, Brown MS | title = Mevinolin, an inhibitor of cholesterol synthesis, induces mRNA for low density lipoprotein receptor in livers of hamsters and rabbits | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 21 | pages = 8370–8374 | date = November 1986 | pmid = 3464957 | pmc = 386930 | doi = 10.1073/pnas.83.21.8370 | doi-access = free | title-link = doi | bibcode = 1986PNAS...83.8370M }}</ref> This is accomplished via [[protease]]s that cleave membrane-bound [[sterol regulatory element binding protein]]s, which then migrate to the [[cell nucleus|nucleus]] and bind to the sterol response elements. The sterol response elements then facilitate increased transcription of various other proteins, most notably, [[LDL receptor]]. The LDL receptor is transported to the liver [[cell membrane]] and binds to passing [[low density lipoprotein|LDL]] and [[very low density lipoprotein|VLDL]] particles, mediating their uptake into the liver, where the cholesterol is reprocessed into bile salts and other byproducts. This results in a net effect of less LDL circulating in blood.{{cn|date=May 2024}}

===Decreasing of specific protein prenylation===
Statins, by inhibiting the HMG CoA reductase pathway, inhibit downstream synthesis of isoprenoids, such as [[farnesyl pyrophosphate]] and [[geranylgeranyl pyrophosphate]]. Inhibition of protein [[prenylation]] for proteins such as [[Transforming protein RhoA|RhoA]] (and subsequent inhibition of [[Rho-associated protein kinase]]) may be involved, at least partially, in the improvement of endothelial function, modulation of immune function, and other [[Pleiotropy|pleiotropic]] cardiovascular benefits of statins,<ref>{{cite journal | vauthors = Laufs U, Custodis F, Böhm M | title = HMG-CoA reductase inhibitors in chronic heart failure: potential mechanisms of benefit and risk | journal = Drugs | volume = 66 | issue = 2 | pages = 145–154 | year = 2006 | pmid = 16451090 | doi = 10.2165/00003495-200666020-00002 | s2cid = 46985044 }}</ref><ref>{{cite journal | vauthors = Greenwood J, Steinman L, Zamvil SS | title = Statin therapy and autoimmune disease: from protein prenylation to immunomodulation | journal = Nature Reviews. Immunology | volume = 6 | issue = 5 | pages = 358–370 | date = May 2006 | pmid = 16639429 | pmc = 3842637 | doi = 10.1038/nri1839 }}</ref><ref>{{cite journal | vauthors = Lahera V, Goicoechea M, de Vinuesa SG, Miana M, de las Heras N, Cachofeiro V, Luño J | title = Endothelial dysfunction, oxidative stress and inflammation in atherosclerosis: beneficial effects of statins | journal = Current Medicinal Chemistry | volume = 14 | issue = 2 | pages = 243–248 | year = 2007 | pmid = 17266583 | doi = 10.2174/092986707779313381 }}</ref><ref name=":1">{{cite journal | vauthors = Blum A, Shamburek R | title = The pleiotropic effects of statins on endothelial function, vascular inflammation, immunomodulation and thrombogenesis | journal = Atherosclerosis | volume = 203 | issue = 2 | pages = 325–330 | date = April 2009 | pmid = 18834985 | doi = 10.1016/j.atherosclerosis.2008.08.022 }}</ref><ref>{{cite journal | vauthors = Porter KE, Turner NA | title = Statins and myocardial remodelling: cell and molecular pathways | journal = Expert Reviews in Molecular Medicine | volume = 13 | issue = e22 | pages = e22 | date = July 2011 | pmid = 21718586 | doi = 10.1017/S1462399411001931 | s2cid = 1975524 }}</ref><ref>{{cite journal | vauthors = Sawada N, Liao JK | title = Rho/Rho-associated coiled-coil forming kinase pathway as therapeutic targets for statins in atherosclerosis | journal = Antioxidants & Redox Signaling | volume = 20 | issue = 8 | pages = 1251–1267 | date = March 2014 | pmid = 23919640 | pmc = 3934442 | doi = 10.1089/ars.2013.5524 }}</ref> as well as in the fact that a number of other drugs that lower LDL have not shown the same cardiovascular risk benefits in studies as statins,<ref>{{cite web | url = http://www.medpagetoday.com/Endocrinology/GeneralEndocrinology/47224 | title = Questions Remain in Cholesterol Research | website = MedPageToday | date = 15 August 2014 | access-date = 27 April 2015 | archive-date = 25 February 2021 | archive-url = https://web.archive.org/web/20210225224042/https://www.medpagetoday.com/endocrinology/generalendocrinology/47224 | url-status = live }}</ref> and may also account for some of the benefits seen in cancer reduction with statins.<ref>{{cite journal | vauthors = Thurnher M, Nussbaumer O, Gruenbacher G | title = Novel aspects of mevalonate pathway inhibitors as antitumor agents | journal = Clinical Cancer Research | volume = 18 | issue = 13 | pages = 3524–3531 | date = July 2012 | pmid = 22529099 | doi = 10.1158/1078-0432.CCR-12-0489 | doi-access = free | title-link = doi }}</ref> In addition, the inhibitory effect on protein prenylation may also be involved in a number of unwanted side effects associated with statins, including muscle pain (myopathy)<ref>{{cite journal | vauthors = Norata GD, Tibolla G, Catapano AL | title = Statins and skeletal muscles toxicity: from clinical trials to everyday practice | journal = Pharmacological Research | volume = 88 | pages = 107–113 | date = October 2014 | pmid = 24835295 | doi = 10.1016/j.phrs.2014.04.012 }}</ref> and elevated blood sugar (diabetes).<ref>{{cite journal | vauthors = Kowluru A | title = Protein prenylation in glucose-induced insulin secretion from the pancreatic islet beta cell: a perspective | journal = Journal of Cellular and Molecular Medicine | volume = 12 | issue = 1 | pages = 164–173 | date = January 2008 | pmid = 18053094 | pmc = 3823478 | doi = 10.1111/j.1582-4934.2007.00168.x }}</ref>

===Other effects===
As noted above, statins exhibit action beyond lipid-lowering activity in the prevention of [[atherosclerosis]] through so-called "pleiotropic effects of statins".<ref name=":1" /> The pleiotropic effects of statins remain controversial.<ref name=":2">{{cite journal | vauthors = Liao JK, Laufs U | title = Pleiotropic effects of statins | journal = Annual Review of Pharmacology and Toxicology | volume = 45 | pages = 89–118 | year = 2005 | pmid = 15822172 | pmc = 2694580 | doi = 10.1146/annurev.pharmtox.45.120403.095748 }}</ref> The ASTEROID trial showed direct [[intravascular ultrasound|ultrasound]] evidence of [[atheroma]] regression during statin therapy.<ref name="Nissen2006">{{cite journal | vauthors = Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, Davignon J, Erbel R, Fruchart JC, Tardif JC, Schoenhagen P, Crowe T, Cain V, Wolski K, Goormastic M, Tuzcu EM | title = Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial | journal = JAMA | volume = 295 | issue = 13 | pages = 1556–1565 | date = April 2006 | pmid = 16533939 | doi = 10.1001/jama.295.13.jpc60002 | doi-access = free | title-link = doi }}</ref> Researchers hypothesize that statins prevent [[cardiovascular disease]] via four proposed mechanisms (all subjects of a large body of biomedical research):<ref name=":2" />

# Improve [[endothelium|endothelial]] function
# Modulate [[inflammation|inflammatory]] responses
# Maintain [[atherosclerosis|plaque]] stability
# Prevent [[thrombosis|blood clot]] formation

In 2008, the [[JUPITER trial]] showed statins provided benefit in those who had no history of [[hyperlipidemia|high cholesterol]] or heart disease, but only in those with elevated high-sensitivity [[C-reactive protein]] (hsCRP) levels, an indicator for inflammation.<ref name="Ridker2008">{{cite journal | vauthors = Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ | title = Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein | journal = The New England Journal of Medicine | volume = 359 | issue = 21 | pages = 2195–2207 | date = November 2008 | pmid = 18997196 | doi = 10.1056/NEJMoa0807646 | doi-access = free | title-link = doi }}</ref> The study has been criticized due to perceived flaws in the study design,<ref>{{cite journal | vauthors = Kones R | title = Rosuvastatin, inflammation, C-reactive protein, JUPITER, and primary prevention of cardiovascular disease—a perspective | journal = Drug Design, Development and Therapy | volume = 4 | pages = 383–413 | date = December 2010 | pmid = 21267417 | pmc = 3023269 | doi = 10.2147/DDDT.S10812 | doi-access = free | title-link = doi }}</ref><ref>{{cite journal | vauthors = Ferdinand KC | title = Are cardiovascular benefits in statin lipid effects dependent on baseline lipid levels? | journal = Current Atherosclerosis Reports | volume = 13 | issue = 1 | pages = 64–72 | date = February 2011 | pmid = 21104458 | doi = 10.1007/s11883-010-0149-9 | s2cid = 32142669 }}</ref><ref>{{cite journal | vauthors = Devaraj S, Siegel D, Jialal I | title = Statin therapy in metabolic syndrome and hypertension post-JUPITER: what is the value of CRP? | journal = Current Atherosclerosis Reports | volume = 13 | issue = 1 | pages = 31–42 | date = February 2011 | pmid = 21046291 | pmc = 3018293 | doi = 10.1007/s11883-010-0143-2 }}</ref> although [[Paul Ridker|Paul M. Ridker]], lead investigator of the JUPITER trial, has responded to these criticisms at length.<ref>{{cite journal | vauthors = Ridker PM, Glynn RJ | title = The JUPITER Trial: responding to the critics | journal = The American Journal of Cardiology | volume = 106 | issue = 9 | pages = 1351–1356 | date = November 2010 | pmid = 21029837 | doi = 10.1016/j.amjcard.2010.08.025 }}</ref>

{{StatinPathway_WP430}}

As the target of statins, the HMG-CoA reductase, is highly similar between [[eukaryota]] and [[archaea]], statins also act as antibiotics against archaea by inhibiting archaeal mevalonate biosynthesis. This has been shown in vivo and in vitro.<ref name="pmid30702149">{{cite journal | vauthors = Vögeli B, Shima S, Erb TJ, Wagner T | title = Crystal structure of archaeal HMG-CoA reductase: insights into structural changes of the C-terminal helix of the class-I enzyme | journal = FEBS Letters | volume = 593 | issue = 5 | pages = 543–553 | date = March 2019 | pmid = 30702149 | doi = 10.1002/1873-3468.13331 | s2cid = 73412833 | doi-access = free | title-link = doi }}</ref> Since patients with a constipation phenotype present with higher abundance of methanogenic archaea in the gut, the use of statins for management of [[irritable bowel syndrome]] has been proposed and may actually be one of the hidden benefits of statin use.<ref name="pmid26559904">{{cite journal | vauthors = Gottlieb K, Wacher V, Sliman J, Pimentel M | title = Review article: inhibition of methanogenic archaea by statins as a targeted management strategy for constipation and related disorders | journal = Alimentary Pharmacology & Therapeutics | volume = 43 | issue = 2 | pages = 197–212 | date = January 2016 | pmid = 26559904 | pmc = 4737270 | doi = 10.1111/apt.13469 }}</ref><ref name="pmid26066650">{{cite journal | vauthors = Lurie-Weinberger MN, Gophna U | title = Archaea in and on the Human Body: Health Implications and Future Directions | journal = PLOS Pathogens | volume = 11 | issue = 6 | pages = e1004833 | date = June 2015 | pmid = 26066650 | pmc = 4466265 | doi = 10.1371/journal.ppat.1004833 | doi-access = free | title-link = doi }}</ref>