Editing Statin (section)

==History==
{{Main|Statin development}}

The role of cholesterol in the development of cardiovascular disease was elucidated in the second half of the 20th century.<ref>{{cite journal | vauthors = Goldstein JL, Brown MS | title = A century of cholesterol and coronaries: from plaques to genes to statins | journal = Cell | volume = 161 | issue = 1 | pages = 161–172 | date = March 2015 | pmid = 25815993 | pmc = 4525717 | doi = 10.1016/j.cell.2015.01.036 }}</ref> This [[lipid hypothesis]] prompted attempts to reduce cardiovascular disease burden by lowering cholesterol. Treatment consisted mainly of [[Diet (nutrition)|dietary measures]], such as a [[low-fat diet]], and poorly tolerated medicines, such as [[clofibrate]], [[cholestyramine]], and [[nicotinic acid]]. Cholesterol researcher Daniel Steinberg writes that while the Coronary Primary Prevention Trial of 1984 demonstrated cholesterol lowering could significantly reduce the risk of heart attacks and angina, physicians, including cardiologists, remained largely unconvinced.<ref>{{cite book | vauthors = Steinberg D | title=The cholesterol wars: the skeptics vs. the preponderance of evidence | publisher=Academic Press | year=2007 | isbn=978-0-12-373979-7 | pages=6–9}}</ref> Scientists in academic settings and the pharmaceutical industry began trying to develop a drug to reduce cholesterol more effectively. There were several potential targets, with 30 steps in the synthesis of cholesterol from acetyl-coenzyme A.<ref>{{cite journal | vauthors = Endo A | title = A historical perspective on the discovery of statins | journal = Proceedings of the Japan Academy. Series B, Physical and Biological Sciences | volume = 86 | issue = 5 | pages = 484–493 | date = 2010 | pmid = 20467214 | pmc = 3108295 | doi = 10.2183/pjab.86.484 | bibcode = 2010PJAB...86..484E }}</ref>

In 1971, [[Akira Endo (biochemist)|Akira Endo]], a Japanese biochemist working for the pharmaceutical company [[Daiichi Sankyo|Sankyo]], began to investigate this problem. Research had already shown cholesterol is mostly manufactured by the body in the liver with the enzyme HMG-CoA reductase.<ref name=Simons/> Endo and his 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 walls or [[cytoskeleton]] ([[isoprenoid]]s).<ref name="Endo1992"/> The first agent they identified was [[mevastatin]] (ML-236B), a molecule produced by the fungus ''[[Penicillium citrinum]]''.{{cn|date=May 2024}}

A British group isolated the same compound from ''Penicillium brevicompactum'', named it [[compactin]], and published their report in 1976.<ref>{{cite journal | vauthors = Brown AG, Smale TC, King TJ, Hasenkamp R, Thompson RH | title = Crystal and molecular structure of compactin, a new antifungal metabolite from Penicillium brevicompactum | journal = Journal of the Chemical Society, Perkin Transactions 1 | issue = 11 | pages = 1165–1170 | year = 1976 | pmid = 945291 | doi = 10.1039/P19760001165 }}</ref> The British group mentions antifungal properties, with no mention of HMG-CoA reductase inhibition.<ref>{{Cite journal |last1=Ko |first1=Humphrey H.T. |last2=Lareu |first2=Ricky R. |last3=Dix |first3=Brett R. |last4=Hughes |first4=Jeffery D. |date=24 October 2017 |title=Statins: antimicrobial resistance breakers or makers? |journal=PeerJ  |volume=5 |pages=e3952 |doi=10.7717/peerj.3952 | doi-access = free | title-link = doi |issn=2167-8359 |pmc=5659212 |pmid=29085751}}</ref><ref>{{Cite journal |last1=Gesto |first1=Diana S. |last2=Pereira |first2=Carlos M. S. |last3=Cerqueira |first3=Nuno M. F. S. |last4=Sousa |first4=Sérgio F. |date=26 August 2020 |title=An Atomic-Level Perspective of HMG-CoA-Reductase: The Target Enzyme to Treat Hypercholesterolemia |journal=Molecules  |volume=25 |issue=17 |pages=3891 |doi=10.3390/molecules25173891 | doi-access = free | title-link = doi |issn=1420-3049 |pmc=7503714 |pmid=32859023}}</ref> Mevastatin was never marketed, because of its adverse effects of tumors, muscle deterioration, and sometimes death in laboratory dogs. [[P. Roy Vagelos]], chief scientist and later CEO of [[Merck & Co]], was interested, and made several trips to Japan starting in 1975. By 1978, Merck had isolated [[lovastatin]] (mevinolin, MK803) from the fungus ''[[Aspergillus terreus]]'', first marketed in 1987 as Mevacor.<ref name="Simons">{{cite journal |vauthors=Simons J |date=January 2003 |title=The $10 billion pill |url=https://money.cnn.com/magazines/fortune/fortune_archive/2003/01/20/335643/index.htm |journal=[[Fortune (magazine)|Fortune]] |volume=147 |issue=1 |pages=58–62, 66, 68 |pmid=12602122}}</ref>

In the 1990s, as a result of public campaigns, people in the United States became familiar with their cholesterol numbers and the difference between HDL and LDL cholesterol, and various pharmaceutical companies began producing their own statins, such as pravastatin (Pravachol), manufactured by Sankyo and [[Bristol-Myers Squibb]]. In April 1994, the results of a Merck-sponsored study, the [[Scandinavian Simvastatin Survival Study]], were announced. Researchers tested [[simvastatin]], later sold by Merck as Zocor, on 4,444 patients with high cholesterol and heart disease. After five years, the study concluded the patients saw a 35% reduction in their cholesterol, and their chances of dying of a heart attack were reduced by 42%.<ref name=Simons/><ref name="4S">{{cite journal | title = Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) | journal = Lancet | volume = 344 | issue = 8934 | pages = 1383–1389 | date = November 1994 | pmid = 7968073 | doi = 10.1016/S0140-6736(94)90566-5 | s2cid = 5965882 | last1 = Scandinaviansimvastatinsurvival }}</ref> In 1995, Zocor and Mevacor both made Merck over {{US$|1 billion}}.<ref name=Simons/>

Though he did not profit from his original discovery, Endo was awarded the 2006 [[Japan Prize]], and the [[Lasker-DeBakey Clinical Medical Research Award]] in 2008, for his pioneering research.<ref>{{cite web |title=National Inventors Hall of Fame Honors 2012 Inductees |url=http://news.thomasnet.com/IMT/2012/05/08/2012-inventors-hall-of-fame-inductees/ |access-date=11 May 2014 |vauthors=Lane B |date=8 May 2012 |archive-date=26 April 2019 |archive-url=https://web.archive.org/web/20190426063759/https://news.thomasnet.com/imt/2012/05/08/2012-inventors-hall-of-fame-inductees |url-status=dead }}</ref> Endo was also inducted into the [[National Inventors Hall of Fame]] in Alexandria, Virginia in 2012. [[Michael S. Brown]] and [[Joseph L. Goldstein|Joseph Goldstein]], who won the Nobel Prize for related work on cholesterol, said of Endo: "The millions of people whose lives will be extended through statin therapy owe it all to Akira Endo."<ref>{{cite news |title=How One Scientist Intrigued by Molds Found First Statin |url=https://www.wsj.com/articles/SB113677121574341250 |work=[[The Wall Street Journal]] |access-date=11 May 2014 |vauthors=Landers P |date=9 January 2006 |url-access=subscription |archive-date=29 May 2020 |archive-url=https://web.archive.org/web/20200529015919/https://www.wsj.com/articles/SB113677121574341250 |url-status=live }}</ref>

{{as of|2016}} misleading claims exaggerating the adverse effects of statins had received widespread media coverage, with a consequent negative impact to public health.<ref name="Collins2016"/> Controversy over the effectiveness of statins in the medical literature was amplified in popular media in the early 2010s, leading an estimated 200,000 people in the UK to stop using statins over a six-month period to mid 2016, according to the authors of a study funded by the British Heart Foundation. They estimated that there could be up to 2,000 extra heart attacks or strokes over the following 10 years as a consequence.<ref>{{cite news | vauthors=Boseley S | title=Statins prevent 80,000 heart attacks and strokes a year in UK, study finds | work=[[The Guardian]] | date=8 September 2016 | url=https://www.theguardian.com/society/2016/sep/08/statins-prevent-80000-heart-attacks-and-strokes-a-year-in-uk-study-finds | access-date=29 December 2017 | archive-date=8 August 2017 | archive-url=https://web.archive.org/web/20170808234418/https://www.theguardian.com/society/2016/sep/08/statins-prevent-80000-heart-attacks-and-strokes-a-year-in-uk-study-finds | url-status=live }}</ref> An unintended effect of the academic statin controversy has been the spread of scientifically questionable [[Alternative medicine|alternative therapies]]. Cardiologist [[Steven Nissen]] at [[Cleveland Clinic]] commented "We are losing the battle for the hearts and minds of our patients to Web sites..."<ref>{{cite web|url=http://www.cardiobrief.org/2017/07/24/nissen-calls-statin-denialism-a-deadly-internet-driven-cult/|archive-url=https://web.archive.org/web/20171219010101/http://www.cardiobrief.org/2017/07/24/nissen%2Dcalls%2Dstatin%2Ddenialism%2Da%2Ddeadly%2Dinternet%2Ddriven%2Dcult/|title=Nissen Calls Statin Denialism A Deadly Internet-Driven Cult| vauthors = Husten L |date=24 July 2017|publisher=CardioBrief|access-date=19 December 2017|url-status=live|archive-date=19 December 2017 }}</ref> promoting unproven medical therapies. [[Harriet Hall]] sees a spectrum of "statin denialism" ranging from [[Pseudoscience|pseudoscientific]] claims to the understatement of benefits and overstatement of side effects, all of which is contrary to the scientific evidence.<ref>{{cite magazine | vauthors = Hall H |author-link1=Harriet Hall |title=Statin Denialism |magazine=Skeptical Inquirer |year=2017 |volume=41 |issue=3 |pages=40–43 |url=https://skepticalinquirer.org/2017/05/statin_denialism/ |archive-url=https://web.archive.org/web/20181006201202/https://www.csicop.org/si/show/statin_denialism |archive-date=6 October 2018 |access-date=6 October 2018 |url-status=live }}</ref>

Several statins have been approved as [[generic drug]]s in the United States:
* Lovastatin (Mevacor) in December 2001<ref>{{cite web | title=First-Time Generics – December 2001 | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/ucm063397.htm | archive-url=https://web.archive.org/web/20090712100155/https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/ucm063397.htm | archive-date=12 July 2009 | access-date=26 April 2020 }}</ref><ref>{{cite web | title=Lovastatin: FDA-Approved Drugs | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=075300 | access-date=12 February 2023}}</ref><ref>{{cite web | url=http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/ucm063397.htm | title=ANDA Approval Reports - First-Time Generics - December 2001 | website=[[Food and Drug Administration]] | access-date=12 February 2023 | url-status=dead | archive-date=13 January 2017 | archive-url=https://wayback.archive-it.org/7993/20170113115145/http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/ucm063397.htm }}</ref>
* Pravastatin (Pravachol) in April 2006<ref>{{cite web | title=First-Time Generics – April 2006 | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/ucm064074.htm | archive-url=https://web.archive.org/web/20090712095947/https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/ucm064074.htm | archive-date=12 July 2009 | access-date=26 April 2020 }}</ref><ref>{{cite web | title=Pravastatin: FDA-Approved Drugs | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=076056 | access-date=12 February 2023 | archive-date=12 February 2023 | archive-url=https://web.archive.org/web/20230212063952/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=076056 | url-status=live }}</ref><ref>{{cite web | url=http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/ucm064074.htm | title=ANDA Approval Reports - First-Time Generics - April 2006 | website=[[Food and Drug Administration]] | access-date=12 February 2023 | url-status=dead | archive-date=13 January 2017 | archive-url=https://wayback.archive-it.org/7993/20170113114626/http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/ucm064074.htm }}</ref>
* Simvastatin (Zocor) in June 2006<ref>{{cite web | title=First-Time Generics – June 2006 | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/ucm064061.htm | archive-url=https://web.archive.org/web/20090712095951/https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/ucm064061.htm | archive-date=12 July 2009 | access-date=26 April 2020}}</ref><ref>{{cite web | title=Simvastatin: FDA-Approved Drugs | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=076052 | access-date=12 February 2023}}</ref><ref>{{cite web | url=http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/ucm064061.htm | title=ANDA Approval Reports - First-Time Generics - June 2006 | website=[[Food and Drug Administration]] | access-date=12 February 2023 | url-status=dead | archive-date=13 January 2017 | archive-url=https://wayback.archive-it.org/7993/20170113114614/http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/ucm064061.htm }}</ref>
* Atorvastatin (Lipitor) in November 2011<ref>{{cite web | vauthors=DeNoon DJ | title=FAQ: Generic Lipitor | website=WebMD | date=29 November 2011 | url=https://www.webmd.com/cholesterol-management/news/20111129/faq-generic-lipitor | access-date=26 April 2020 | archive-date=5 August 2020 | archive-url=https://web.archive.org/web/20200805225928/https://www.webmd.com/cholesterol-management/news/20111129/faq-generic-lipitor | url-status=live }}</ref><ref>{{cite web | title=First-Time Generic Drug Approvals – November 2011 | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/ucm282392.htm | archive-url=https://web.archive.org/web/20111208184841/https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/ucm282392.htm | archive-date=8 December 2011 | access-date=26 April 2020 }}</ref><ref>{{cite web | title=Atorvastatin: FDA-Approved Drugs | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=076477 | access-date=12 February 2023 | archive-date=12 February 2023 | archive-url=https://web.archive.org/web/20230212062449/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=076477 | url-status=live }}</ref><ref>{{cite web | url=http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/ucm282392.htm | title=ANDA Approval Reports - First-Time Generic Drug Approvals - November 2011 | website=[[Food and Drug Administration]] | access-date=12 February 2023 | url-status=dead | archive-date=13 January 2017 | archive-url=https://wayback.archive-it.org/7993/20170113114412/http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/ucm282392.htm }}</ref>
* Fluvastatin (Lescol) in April 2012<ref>{{cite web | title=First-Time Generic Drug Approvals – April 2012 | website=U.S. [[Food and Drug Administration]] (FDA) | url=https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/ucm312283.htm | archive-url=https://web.archive.org/web/20120719225232/https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/ucm312283.htm | archive-date=19 July 2012 | access-date=26 April 2020}}</ref><ref>{{cite web | url=http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/ucm312283.htm | title=ANDA Approval Reports - First-Time Generic Drug Approvals - April 2012 | website=[[Food and Drug Administration]] | access-date=12 February 2023 | url-status=dead | archive-date=13 January 2017 | archive-url=https://wayback.archive-it.org/7993/20170113114358/http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/ucm312283.htm }}</ref>
* Pitavastatin (Livalo) and rosuvastatin (Crestor) in 2016<ref>{{cite web | title=ANDA (Generic) Drug Approvals in 2016 | website=U.S. [[Food and Drug Administration]] (FDA) | date=3 November 2018 | url=https://www.fda.gov/drugs/first-generic-drug-approvals/anda-generic-drug-approvals-2016 | access-date=26 April 2020 | archive-date=11 August 2020 | archive-url=https://web.archive.org/web/20200811020044/https://www.fda.gov/drugs/first-generic-drug-approvals/anda-generic-drug-approvals-2016 | url-status=live }}</ref><ref>{{cite press release | title=FDA approves first generic Crestor | website=U.S. [[Food and Drug Administration]] (FDA) | date=29 April 2016 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-generic-crestor | access-date=26 April 2020 | archive-date=15 March 2020 | archive-url=https://web.archive.org/web/20200315024145/https://www.fda.gov/news-events/press-announcements/fda-approves-first-generic-crestor | url-status=live }}</ref>
* Ezetimibe/simvastatin (Vytorin) and ezetimibe/atorvastatin (Liptruzet) in 2017<ref name="CDER 2017">{{cite web | title=CDER 2017 First Generic Drug Approvals | website=U.S. [[Food and Drug Administration]] (FDA) | date=3 November 2018 | url=https://www.fda.gov/drugs/first-generic-drug-approvals/2017-first-generic-drug-approvals | access-date=26 April 2020 | archive-date=26 April 2020 | archive-url=https://web.archive.org/web/20200426185216/https://www.fda.gov/drugs/first-generic-drug-approvals/2017-first-generic-drug-approvals | url-status=live }}</ref>