Statin#Primary prevention

Statins are usually used to lower blood cholesterol levels and reduce risk for illnesses related to atherosclerosis, with a varying degree of effect depending on underlying risk factors and history of cardiovascular disease.{{Cite journal |last1=Tunnicliffe |first1=David J. |last2=Palmer |first2=Suetonia C. |last3=Cashmore |first3=Brydee A. |last4=Saglimbene |first4=Valeria M. |last5=Krishnasamy |first5=Rathika |last6=Lambert |first6=Kelly |last7=Johnson |first7=David W. |last8=Craig |first8=Jonathan C. |last9=Strippoli |first9=Giovanni Fm |date=29 November 2023 |title=HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis |journal=The Cochrane Database of Systematic Reviews |volume=11 |issue=11 |pages=CD007784 |doi=10.1002/14651858.CD007784.pub3 |issn=1469-493X |pmc=10685396 |pmid=38018702 }} A 2022 systematic review found the absolute risk reductions for three hard outcomes – all-cause mortality, myocardial infarction, and stroke – to be 0.8%, 1.3%, and 0.4%, respectively (relative risk: 9%, 29%, 14%). The association between effect size and LDL cholesterol reduction was unclear, and there was significant clinical and statistical heterogeneity between trials.{{cite journal |vauthors=Byrne P, Demasi M, Jones M, Smith SM, O'Brien KK, DuBroff R |title=Evaluating the Association Between Low-Density Lipoprotein Cholesterol Reduction and Relative and Absolute Effects of Statin Treatment: A Systematic Review and Meta-analysis |journal=JAMA Internal Medicine |volume=182 | issue=5 |pages=474–481 |date=May 2022 |pmid=35285850 |pmc=8922205 |doi=10.1001/jamainternmed.2022.0134 | doi-access=free}} Clinical practice guidelines generally recommend that people at low risk start with lifestyle modification through a cholesterol-lowering diet and physical exercise; for those unable to meet their lipid-lowering goals through such methods, statins can be helpful.{{cite book |author=National Cholesterol Education Program |title=Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): Executive Summary |publisher=National Institutes of Health. National Heart, Lung, and Blood Institute |year=2001 |location=Bethesda, MD |page=40 |id=NIH Publication No. 01-3670}}{{cite book | author=National Collaborating Centre for Primary Care | title=NICE clinical guideline 67: Lipid modification | location=London | publisher=National Institute for Health and Clinical Excellence | year=2010 | page=38 | url=http://www.nice.org.uk/nicemedia/live/11982/40689/40689.pdf | archive-url=https://web.archive.org/web/20101010200351/http://www.nice.org.uk/nicemedia/live/11982/40689/40689.pdf | archive-date=10 October 2010 | df=dmy-all }} The medication appears to work equally well regardless of sex,{{cite journal |author-link9=Rory Collins |vauthors=Fulcher J, O'Connell R, Voysey M, Emberson J, Blackwell L, Mihaylova B, Simes J, Collins R, Kirby A, Colhoun H, Braunwald E, La Rosa J, Pedersen TR, Tonkin A, Davis B, Sleight P, Franzosi MG, Baigent C, Keech A |date=April 2015 |title=Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials |journal=The Lancet |volume=385 |issue=9976 |pages=1397–1405 |doi=10.1016/s0140-6736(14)61368-4 |pmid=25579834 |s2cid=35330627 |hdl-access=free |hdl=2123/14127}} although some sex-related differences in treatment response were described.{{cite journal |vauthors=Cangemi R, Romiti GF, Campolongo G, Ruscio E, Sciomer S, Gianfrilli D, Raparelli V |date=March 2017 |title=Gender related differences in treatment and response to statins in primary and secondary cardiovascular prevention: The never-ending debate |journal=Pharmacological Research |volume=117 |pages=148–155 |doi=10.1016/j.phrs.2016.12.027 |pmid=28012963 |s2cid=32861954}}

If there is an underlying history of cardiovascular disease, it has a significant impact on the effects of statin. This can be used to divide medication usage into broad categories of primary and secondary prevention.{{cite journal |vauthors=Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC, Sperling L, Virani SS, Yeboah J |date=June 2019 |title=2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines |journal=Journal of the American College of Cardiology |volume=73 |issue=24 |pages=e285–e350 |doi=10.1016/j.jacc.2018.11.003 |pmid=30423393 | doi-access = free | title-link = doi |hdl-access=free |hdl=20.500.12749/1738}}

For the primary prevention of cardiovascular disease, the United States Preventive Services Task Force (USPSTF) 2016 guidelines recommend statins for those who have at least one risk factor for coronary heart disease, are between 40 and 75 years old, and have at least a 10% 10-year risk of heart disease, as calculated by the 2013 ACC/AHA Pooled Cohort algorithm.{{cite web |title=ACC/AHA ASCVD Risk Calculator |url=http://www.cvriskcalculator.com/ |website=www.cvriskcalculator.com |access-date=8 March 2019 |archive-date=9 March 2019 |archive-url=https://web.archive.org/web/20190309213928/http://www.cvriskcalculator.com/ }} Risk factors for coronary heart disease included abnormal lipid levels in the blood, diabetes mellitus, high blood pressure, and smoking.{{cite journal | vauthors = Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW, García FA, Gillman MW, Kemper AR, Krist AH, Kurth AE, Landefeld CS, LeFevre ML, Mangione CM, Phillips WR, Owens DK, Phipps MG, Pignone MP | title = Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: US Preventive Services Task Force Recommendation Statement | journal = JAMA | volume = 316 | issue = 19 | pages = 1997–2007 | date = November 2016 | pmid = 27838723 | doi = 10.1001/jama.2016.15450 | s2cid = 205075217 }} They recommended selective use of low-to-moderate doses statins in the same adults who have a calculated 10-year cardiovascular disease event risk of 7.5–10% or greater. In people over the age of 70, statins decrease the risk of cardiovascular disease but only in those with a history of heavy cholesterol blockage in their arteries.{{cite journal | title = Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials | journal = Lancet | volume = 393 | issue = 10170 | pages = 407–415 | date = February 2019 | pmid = 30712900 | pmc = 6429627 | doi = 10.1016/S0140-6736(18)31942-1 | vauthors = Armitage J, Baigent C, Barnes E, Betteridge DJ, Blackwell L, Blazing M, Bowman L, Braunwald E, Byington R, Cannon C, Clearfield M, Colhoun H, Collins R, Dahlöf B, Davies K, Davis B, De Lemos J, Downs JR, Durrington P, Emberson J, Fellström B, Flather M, Ford I, Franzosi MG, Fulcher J, Fuller J, Furberg C, Gordon D, Goto S, Gotto A }}

Most evidence suggests that statins are also effective in preventing heart disease in those with high cholesterol but no history of heart disease. A 2013 Cochrane review found a decrease in risk of death and other poor outcomes without any evidence of harm. For every 138 people treated for 5 years, one fewer dies; for every 49 treated, one fewer has an episode of heart disease. A 2011 review reached similar conclusions, and a 2012 review found benefits in both women and men.{{cite journal | vauthors = Kostis WJ, Cheng JQ, Dobrzynski JM, Cabrera J, Kostis JB | title = Meta-analysis of statin effects in women versus men | journal = Journal of the American College of Cardiology | volume = 59 | issue = 6 | pages = 572–582 | date = February 2012 | pmid = 22300691 | doi = 10.1016/j.jacc.2011.09.067 | doi-access = free | title-link = doi }} A 2010 review concluded that treatment without history of cardiovascular disease reduces cardiovascular events in men but not women, and provides no mortality benefit in either sex.{{cite journal | vauthors = Petretta M, Costanzo P, Perrone-Filardi P, Chiariello M | title = Impact of gender in primary prevention of coronary heart disease with statin therapy: a meta-analysis | journal = International Journal of Cardiology | volume = 138 | issue = 1 | pages = 25–31 | date = January 2010 | pmid = 18793814 | doi = 10.1016/j.ijcard.2008.08.001 }} Two other meta-analyses published that year, one of which used data obtained exclusively from women, found no mortality benefit in primary prevention.{{cite journal | vauthors = Ray KK, Seshasai SR, Erqou S, Sever P, Jukema JW, Ford I, Sattar N | title = Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants | journal = Archives of Internal Medicine | volume = 170 | issue = 12 | pages = 1024–1031 | date = June 2010 | pmid = 20585067 | doi = 10.1001/archinternmed.2010.182 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Bukkapatnam RN, Gabler NB, Lewis WR | title = Statins for primary prevention of cardiovascular mortality in women: a systematic review and meta-analysis | journal = Preventive Cardiology | volume = 13 | issue = 2 | pages = 84–90 | year = 2010 | pmid = 20377811 | doi = 10.1111/j.1751-7141.2009.00059.x | doi-access = free | title-link = doi }}

The National Institute for Health and Clinical Excellence (NICE) recommends statin treatment for adults with an estimated 10 year risk of developing cardiovascular disease that is greater than 10%.{{cite web |url=http://www.nice.org.uk/guidance/cg181/chapter/1-recommendations |title=Cardiovascular disease: risk assessment and reduction, including lipid modification at www.nice.org.uk |date=18 July 2014 |access-date=1 May 2017 |archive-date=12 June 2018 |archive-url=https://web.archive.org/web/20180612162609/https://www.nice.org.uk/guidance/cg181/chapter/1-recommendations |url-status=live }} Guidelines by the American College of Cardiology and the American Heart Association recommend statin treatment for primary prevention of cardiovascular disease in adults with LDL cholesterol ≥ 190 mg/dL (4.9 mmol/L) or those with diabetes, age 40–75 with LDL-C 70–190 mg/dL (1.8–4.9 mmol/dL); or in those with a 10-year risk of developing heart attack or stroke of 7.5% or more. In this latter group, statin assignment was not automatic, but was recommended to occur only after a clinician-patient risk discussion with shared decision making where other risk factors and lifestyle are addressed, the potential for benefit from a statin is weighed against the potential for adverse effects or drug interactions and informed patient preference is elicited. Moreover, if a risk decision was uncertain, factors such as family history, coronary calcium score, ankle-brachial index, and an inflammation test (hs-CRP ≥ 2.0 mg/L) were suggested to inform the risk decision. Additional factors that could be used were an LDL-C ≥ 160 mg/dL (4.14 mmol/L) or a very high lifetime risk.{{cite journal | vauthors = Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC, Watson K, Wilson PW, Eddleman KM, Jarrett NM, LaBresh K, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC, Tomaselli GF | title = 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines | journal = Circulation | volume = 129 | issue = 25 Suppl 2 | pages = S1-45 | date = June 2014 | pmid = 24222016 | doi = 10.1161/01.cir.0000437738.63853.7a | author-link3 = Alice H. Lichtenstein | doi-access = free | title-link = doi }} However, critics such as Steven E. Nissen say that the AHA/ACC guidelines were not properly validated, overestimate the risk by at least 50%, and recommend statins for people who will not benefit, based on populations whose observed risk is lower than predicted by the guidelines.{{cite journal | vauthors = Nissen SE | title = Prevention guidelines: bad process, bad outcome | journal = JAMA Internal Medicine | volume = 174 | issue = 12 | pages = 1972–1973 | date = December 2014 | pmid = 25285604 | doi = 10.1001/jamainternmed.2014.3278 }} The European Society of Cardiology and the European Atherosclerosis Society recommend the use of statins for primary prevention, depending on baseline estimated cardiovascular score and LDL thresholds.{{cite journal | vauthors = Reiner Ž, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegría E, Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs RH, Kjekshus JK, Perrone Filardi P, Riccardi G, Storey RF, David W | title = [ESC/EAS Guidelines for the management of dyslipidaemias] | journal = Revista Espanola de Cardiologia | volume = 64 | issue = 12 | pages = 1168.e1–1168.e60 | date = December 2011 | pmid = 22115524 | doi = 10.1016/j.rec.2011.09.015 | hdl = 2268/205760 }}

Statins are effective in decreasing mortality in people with pre-existing cardiovascular disease. Pre-existing disease can have many manifestations. Defining illnesses include a prior heart attack, stroke, stable or unstable angina, aortic aneurysm, or other arterial ischemic disease, in the presence of atherosclerosis. They are also advocated for use in people at high risk of developing coronary heart disease.{{cite web |author=National Institute for Health and Clinical Excellence |author-link=National Institute for Health and Clinical Excellence |title=Lipid modification – Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease – Quick reference guide |url=http://www.nice.org.uk/nicemedia/live/11982/40675/40675.pdf |archive-url=https://web.archive.org/web/20110408210750/http://www.nice.org.uk/nicemedia/live/11982/40675/40675.pdf |archive-date=8 April 2011 |orig-date=May 2008 |date=March 2010 |access-date=25 August 2010}} On average, statins can lower LDL cholesterol by 1.8 mmol/L (70 mg/dL), which translates into an estimated 60% decrease in the number of cardiac events (heart attack, sudden cardiac death) and a 17% reduced risk of stroke after long-term treatment.{{cite journal | vauthors = Law MR, Wald NJ, Rudnicka AR | title = Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis | journal = BMJ | volume = 326 | issue = 7404 | pages = 1423–0 | date = June 2003 | pmid = 12829554 | pmc = 162260 | doi = 10.1136/bmj.326.7404.1423 }} A greater benefit is observed with high-intensity statin therapy.{{cite journal | vauthors = Pisaniello AD, Scherer DJ, Kataoka Y, Nicholls SJ | title = Ongoing challenges for pharmacotherapy for dyslipidemia | journal = Expert Opinion on Pharmacotherapy | volume = 16 | issue = 3 | pages = 347–356 | date = February 2015 | pmid = 25476544 | doi = 10.1517/14656566.2014.986094 | s2cid = 539314 }} They have less effect than the fibrates or niacin in reducing triglycerides and raising HDL-cholesterol ("good cholesterol").{{cite journal | vauthors = Kushner PA, Cobble ME | title = Hypertriglyceridemia: the importance of identifying patients at risk | journal = Postgraduate Medicine | volume = 128 | issue = 8 | pages = 848–858 | date = November 2016 | pmid = 27710158 | doi = 10.1080/00325481.2016.1243005 | type = Review | s2cid = 45663315 }}{{cite journal | vauthors = Khera AV, Plutzky J | title = Management of low levels of high-density lipoprotein-cholesterol | journal = Circulation | volume = 128 | issue = 1 | pages = 72–78 | date = July 2013 | pmid = 23817482 | pmc = 4231714 | doi = 10.1161/CIRCULATIONAHA.112.000443 | type = Review }}

No studies have examined the effect of statins on cognition in patients with prior stroke. However, two large studies (HPS and PROSPER) that included people with vascular diseases reported that simvastatin and pravastatin did not impact cognition.{{cite journal | vauthors = Mijajlović MD, Pavlović A, Brainin M, Heiss WD, Quinn TJ, Ihle-Hansen HB, Hermann DM, Assayag EB, Richard E, Thiel A, Kliper E, Shin YI, Kim YH, Choi S, Jung S, Lee YB, Sinanović O, Levine DA, Schlesinger I, Mead G, Milošević V, Leys D, Hagberg G, Ursin MH, Teuschl Y, Prokopenko S, Mozheyko E, Bezdenezhnykh A, Matz K, Aleksić V, Muresanu D, Korczyn AD, Bornstein NM | title = Post-stroke dementia - a comprehensive review | journal = BMC Medicine | volume = 15 | issue = 1 | pages = 11 | date = January 2017 | pmid = 28095900 | pmc = 5241961 | doi = 10.1186/s12916-017-0779-7 | doi-access = free | title-link = doi }}

Statins have been studied for improving operative outcomes in cardiac and vascular surgery.{{cite journal | vauthors = de Waal BA, Buise MP, van Zundert AA | title = Perioperative statin therapy in patients at high risk for cardiovascular morbidity undergoing surgery: a review | journal = British Journal of Anaesthesia | volume = 114 | issue = 1 | pages = 44–52 | date = January 2015 | pmid = 25186819 | doi = 10.1093/bja/aeu295 | doi-access = free | title-link = doi }} Mortality and adverse cardiovascular events were reduced in statin groups.{{cite journal | vauthors = Antoniou GA, Hajibandeh S, Hajibandeh S, Vallabhaneni SR, Brennan JA, Torella F | title = Meta-analysis of the effects of statins on perioperative outcomes in vascular and endovascular surgery | journal = Journal of Vascular Surgery | volume = 61 | issue = 2 | pages = 519–532.e1 | date = February 2015 | pmid = 25498191 | doi = 10.1016/j.jvs.2014.10.021 | doi-access = free | title-link = doi }}

Older adults who receive statin therapy at time of discharge from the hospital after an inpatient stay have been studied. People with cardiac ischemia not previously on statins at the time of admission have a lower risk of major cardiac adverse events and hospital readmission two years post-hospitalization.{{cite journal | vauthors = Sladojevic N, Yu B, Liao JK | title = ROCK as a therapeutic target for ischemic stroke | journal = Expert Review of Neurotherapeutics | volume = 17 | issue = 12 | pages = 1167–1177 | date = December 2017 | pmid = 29057688 | pmc = 6221831 | doi = 10.1080/14737175.2017.1395700 }}{{cite journal | vauthors = Li YH, Ueng KC, Jeng JS, Charng MJ, Lin TH, Chien KL, Wang CY, Chao TH, Liu PY, Su CH, Chien SC, Liou CW, Tang SC, Lee CC, Yu TY, Chen JW, Wu CC, Yeh HI | title = 2017 Taiwan lipid guidelines for high risk patients | journal = Journal of the Formosan Medical Association = Taiwan Yi Zhi | volume = 116 | issue = 4 | pages = 217–248 | date = April 2017 | pmid = 28242176 | doi = 10.1016/j.jfma.2016.11.013 | doi-access = free | title-link = doi }}

All statins appear effective regardless of potency or degree of cholesterol reduction.{{cite journal | vauthors = Tonelli M, Lloyd A, Clement F, Conly J, Husereau D, Hemmelgarn B, Klarenbach S, McAlister FA, Wiebe N, Manns B | title = Efficacy of statins for primary prevention in people at low cardiovascular risk: a meta-analysis | journal = CMAJ | volume = 183 | issue = 16 | pages = E1189–E1202 | date = November 2011 | pmid = 21989464 | pmc = 3216447 | doi = 10.1503/cmaj.101280 }}{{Cite journal |last1=Sheng |first1=Xia |last2=Murphy |first2=Michael J. |last3=MacDonald |first3=Thomas M. |last4=Wei |first4=Li |date=30 August 2012 |title=The comparative effectiveness of statin therapy in selected chronic diseases compared with the remaining population |journal=BMC Public Health |volume=12 |issue=1 |pages=712 |doi=10.1186/1471-2458-12-712 |issn=1471-2458 |pmc=3490740 |pmid=22935195 | doi-access = free | title-link = doi }}{{Cite web |title=Assessing Severity of Statin Side Effects: Fact Versus Fiction |url=https://www.acc.org/Latest-in-Cardiology/Articles/2018/04/09/13/25/http%3a%2f%2fwww.acc.org%2fLatest-in-Cardiology%2fArticles%2f2018%2f04%2f09%2f13%2f25%2fAssessing-Severity-of-Statin-Side-Effects |access-date=11 November 2023 |website=American College of Cardiology}} Simvastatin and pravastatin appear to have a reduced incidence of side-effects.{{Citation |last1=Bansal |first1=Agam B. |title=HMG-CoA Reductase Inhibitors |date=2023 |url=http://www.ncbi.nlm.nih.gov/books/NBK542212/ |work=StatPearls |access-date=11 November 2023 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=31194369 |last2=Cassagnol |first2=Manouchkathe}}{{Cite journal |last1=Zhang |first1=Xiaodan |last2=Xing |first2=Lu |last3=Jia |first3=Xiaona |last4=Pang |first4=Xiaocong |last5=Xiang |first5=Qian |last6=Zhao |first6=Xia |last7=Ma |first7=Lingyue |last8=Liu |first8=Zhiyan |last9=Hu |first9=Kun |last10=Wang |first10=Zhe |last11=Cui |first11=Yimin |date=27 April 2020 |title=Comparative Lipid-Lowering/Increasing Efficacy of 7 Statins in Patients with Dyslipidemia, Cardiovascular Diseases, or Diabetes Mellitus: Systematic Review and Network Meta-Analyses of 50 Randomized Controlled Trials |journal=Cardiovascular Therapeutics |volume=2020 |pages=e3987065 |doi=10.1155/2020/3987065 |issn=1755-5914| doi-access = free | title-link = doi |pmid=32411300 |pmc=7201823 }}

According to the 2015 Cochrane systematic review, atorvastatin showed greater cholesterol-lowering effect in women than in men compared to rosuvastatin.{{cite journal |vauthors=Adams SP, Tsang M, Wright JM |date=March 2015 |title=Lipid-lowering efficacy of atorvastatin |journal=The Cochrane Database of Systematic Reviews |volume=2015 |issue=3 |pages=CD008226 |doi=10.1002/14651858.CD008226.pub3 |pmc=6464917 |pmid=25760954}}

In children, statins are effective at reducing cholesterol levels in those with familial hypercholesterolemia.{{cite journal | vauthors = Vuorio A, Kuoppala J, Kovanen PT, Humphries SE, Tonstad S, Wiegman A, Drogari E, Ramaswami U | title = Statins for children with familial hypercholesterolemia | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | issue = 11 | date = November 2019 | pmid = 31696945 | pmc = 6836374 | doi = 10.1002/14651858.CD006401.pub5 }} Their long term safety is, however, unclear.{{cite journal | vauthors = Lamaida N, Capuano E, Pinto L, Capuano E, Capuano R, Capuano V | title = The safety of statins in children | journal = Acta Paediatrica | volume = 102 | issue = 9 | pages = 857–862 | date = September 2013 | pmid = 23631461 | doi = 10.1111/apa.12280 | s2cid = 22846175 }} Some recommend that if lifestyle changes are not enough statins should be started at 8 years old.{{cite journal | vauthors = Braamskamp MJ, Wijburg FA, Wiegman A | title = Drug therapy of hypercholesterolaemia in children and adolescents | journal = Drugs | volume = 72 | issue = 6 | pages = 759–772 | date = April 2012 | pmid = 22512364 | doi = 10.2165/11632810-000000000-00000 | s2cid = 21141894 }}

Statins may be less effective in reducing LDL cholesterol in people with familial hypercholesterolemia, especially those with homozygous deficiencies. These people have defects usually in either the LDL receptor or apolipoprotein B genes, both of which are responsible for LDL clearance from the blood.{{cite journal | vauthors = Ramasamy I | title = Update on the molecular biology of dyslipidemias | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 454 | pages = 143–185 | date = February 2016 | pmid = 26546829 | doi = 10.1016/j.cca.2015.10.033 }} Statins remain a first-line treatment in familial hypercholesterolemia,{{cite journal | vauthors = Repas TB, Tanner JR | title = Preventing early cardiovascular death in patients with familial hypercholesterolemia | journal = The Journal of the American Osteopathic Association | volume = 114 | issue = 2 | pages = 99–108 | date = February 2014 | pmid = 24481802 | doi = 10.7556/jaoa.2014.023 | doi-access = free | title-link = doi }} although other cholesterol-reducing measures may be required.{{cite journal | vauthors = Rader DJ, Cohen J, Hobbs HH | title = Monogenic hypercholesterolemia: new insights in pathogenesis and treatment | journal = The Journal of Clinical Investigation | volume = 111 | issue = 12 | pages = 1795–1803 | date = June 2003 | pmid = 12813012 | pmc = 161432 | doi = 10.1172/JCI18925 }} In people with homozygous deficiencies, statins may still prove helpful, albeit at high doses and in combination with other cholesterol-reducing medications.{{cite journal | vauthors = Marais AD, Blom DJ, Firth JC | title = Statins in homozygous familial hypercholesterolemia | journal = Current Atherosclerosis Reports | volume = 4 | issue = 1 | pages = 19–25 | date = January 2002 | pmid = 11772418 | doi = 10.1007/s11883-002-0058-7 | s2cid = 8075552 }}

A 2014 meta-analysis found that statins could reduce the risk of contrast-induced nephropathy by 53% in people undergoing coronary angiography/percutaneous interventions. The effect was found to be stronger among those with preexisting kidney dysfunction or diabetes mellitus.{{cite journal | vauthors = Liu YH, Liu Y, Duan CY, Tan N, Chen JY, Zhou YL, Li LW, He PC | title = Statins for the Prevention of Contrast-Induced Nephropathy After Coronary Angiography/Percutaneous Interventions: A Meta-analysis of Randomized Controlled Trials | journal = Journal of Cardiovascular Pharmacology and Therapeutics | volume = 20 | issue = 2 | pages = 181–192 | date = March 2015 | pmid = 25193735 | doi = 10.1177/1074248414549462 | s2cid = 28251228 | doi-access = free | title-link = doi }}

The risk of cardiovascular disease is similar in people with chronic kidney disease and coronary artery disease and statins are often suggested. There is some evidence that appropriate use of statin medications in people with chronic kidney disease who do not require dialysis may reduce mortality and the incidence of major cardiac events by up to 20% and are not that likely to increase the risk of stroke or kidney failure.

Asthma

Statins have been identified as having a possible adjunct role in the treatment of asthma through anti-inflammatory pathways.{{cite journal | vauthors = Naing C, Ni H | title = Statins for asthma | journal = The Cochrane Database of Systematic Reviews | volume = 2020 | issue = 7 | pages = CD013268 | date = July 2020 | pmid = 32668027 | pmc = 7388183 | doi = 10.1002/14651858.CD013268.pub2 | collaboration = Cochrane Airways Group }} There is low quality evidence for the use of statins in treating asthma, however further research is required to determine the effectiveness and safety of this therapy in those with asthma.

The most important adverse side effects are muscle problems, an increased risk of diabetes mellitus, and increased liver enzymes in the blood due to liver damage.{{cite journal | vauthors = Bellosta S, Corsini A | title = Statin drug interactions and related adverse reactions | journal = Expert Opinion on Drug Safety | volume = 11 | issue = 6 | pages = 933–946 | date = November 2012 | pmid = 22866966 | doi = 10.1517/14740338.2012.712959 | s2cid = 6247572 }} Over 5 years of treatment statins result in 75 cases of diabetes, 7.5 cases of bleeding stroke, and 5 cases of muscle damage per 10,000 people treated.{{cite journal | vauthors = Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, Blumenthal R, Danesh J, Smith GD, DeMets D, Evans S, Law M, MacMahon S, Martin S, Neal B, Poulter N, Preiss D, Ridker P, Roberts I, Rodgers A, Sandercock P, Schulz K, Sever P, Simes J, Smeeth L, Wald N, Yusuf S, Peto R | title = Interpretation of the evidence for the efficacy and safety of statin therapy | journal = Lancet | volume = 388 | issue = 10059 | pages = 2532–2561 | date = November 2016 | pmid = 27616593 | doi = 10.1016/S0140-6736(16)31357-5 | type = Submitted manuscript | s2cid = 4641278 | doi-access = free | title-link = doi | hdl = 10044/1/43661 | hdl-access = free }} This could be due to the statins inhibiting the enzyme (HMG-CoA reductase), which is necessary to make cholesterol, but also for other processes, such as CoQ₁₀ production, which is important for muscle function and sugar regulation.{{cite journal | vauthors = Brault M, Ray J, Gomez YH, Mantzoros CS, Daskalopoulou SS | title = Statin treatment and new-onset diabetes: a review of proposed mechanisms | journal = Metabolism | volume = 63 | issue = 6 | pages = 735–745 | date = June 2014 | pmid = 24641882 | doi = 10.1016/j.metabol.2014.02.014 }}

Other possible adverse effects include neuropathy,{{cite journal | vauthors = Jones MR, Urits I, Wolf J, Corrigan D, Colburn L, Peterson E, Williamson A, Viswanath O | title = Drug-Induced Peripheral Neuropathy: A Narrative Review | journal = Current Clinical Pharmacology | volume = 15 | issue = 1 | pages = 38–48 | date = 5 May 2020 | pmid = 30666914 | pmc = 7365998 | doi = 10.2174/1574884714666190121154813 }}{{cite journal | vauthors = Lehrer S, Rheinstein PH | title = Statins combined with niacin reduce the risk of peripheral neuropathy | journal = International Journal of Functional Nutrition | volume = 1 | issue = 1 | date = 9 June 2020 | pmid = 33330853 | pmc = 7737454 | doi = 10.3892/ijfn.2020.3 }} pancreatic and liver dysfunction, and sexual dysfunction. The rate at which such events occur has been widely debated, in part because the risk/benefit ratio of statins in low-risk populations is highly dependent on the rate of adverse events.{{cite journal | vauthors = Kmietowicz Z | title = New analysis fuels debate on merits of prescribing statins to low risk people | journal = BMJ | volume = 348 | pages = g2370 | date = March 2014 | pmid = 24671956 | doi = 10.1136/bmj.g2370 | s2cid = 46535820 }}{{cite journal | vauthors = Wise J | title = Open letter raises concerns about NICE guidance on statins | journal = BMJ | volume = 348 | pages = g3937 | date = June 2014 | pmid = 24920699 | doi = 10.1136/bmj.g3937 | s2cid = 42422361 }}{{cite journal | vauthors = Gøtzsche PC | title = Muscular adverse effects are common with statins | journal = BMJ | volume = 348 | pages = g3724 | date = June 2014 | pmid = 24920687 | doi = 10.1136/bmj.g3724 | s2cid = 206902546 }} A Cochrane meta-analysis of statin clinical trials in primary prevention found no evidence of excess adverse events among those treated with statins compared to placebo. Another meta-analysis found a 39% increase in adverse events in statin treated people relative to those receiving placebo, but no increase in serious adverse events.{{cite journal | vauthors = Silva MA, Swanson AC, Gandhi PJ, Tataronis GR | title = Statin-related adverse events: a meta-analysis | journal = Clinical Therapeutics | volume = 28 | issue = 1 | pages = 26–35 | date = January 2006 | pmid = 16490577 | doi = 10.1016/j.clinthera.2006.01.005 }} The author of one study argued that adverse events are more common in clinical practice than in randomized clinical trials.{{cite journal | vauthors = Golomb BA, Evans MA | title = Statin adverse effects : a review of the literature and evidence for a mitochondrial mechanism | journal = American Journal of Cardiovascular Drugs | volume = 8 | issue = 6 | pages = 373–418 | year = 2008 | pmid = 19159124 | pmc = 2849981 | doi = 10.2165/0129784-200808060-00004 }} A systematic review concluded that while clinical trial meta-analyses underestimate the rate of muscle pain associated with statin use, the rates of rhabdomyolysis are still "reassuringly low" and similar to those seen in clinical trials (about 1–2 per 10,000 person years).{{cite journal | vauthors = Mancini GB, Baker S, Bergeron J, Fitchett D, Frohlich J, Genest J, Gupta M, Hegele RA, Ng D, Pope J | title = Diagnosis, prevention, and management of statin adverse effects and intolerance: proceedings of a Canadian Working Group Consensus Conference | journal = The Canadian Journal of Cardiology | volume = 27 | issue = 5 | pages = 635–662 | year = 2011 | pmid = 21963058 | doi = 10.1016/j.cjca.2011.05.007 }} Another systematic review from the International Centre for Circulatory Health of the National Heart and Lung Institute in London concluded that only a small fraction of side effects reported by people on statins are actually attributable to the statin.{{cite journal | vauthors = Finegold JA, Manisty CH, Goldacre B, Barron AJ, Francis DP | title = What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choice | journal = European Journal of Preventive Cardiology | volume = 21 | issue = 4 | pages = 464–474 | date = April 2014 | pmid = 24623264 | doi = 10.1177/2047487314525531 | s2cid = 21064267 | doi-access = free | title-link = doi }}

Multiple systematic reviews and meta-analyses have concluded that the available evidence does not support an association between statin use and cognitive decline.{{cite journal | vauthors = Swiger KJ, Manalac RJ, Blumenthal RS, Blaha MJ, Martin SS | title = Statins and cognition: a systematic review and meta-analysis of short- and long-term cognitive effects | journal = Mayo Clinic Proceedings | volume = 88 | issue = 11 | pages = 1213–1221 | date = November 2013 | pmid = 24095248 | doi = 10.1016/j.mayocp.2013.07.013 }}{{cite journal | vauthors = Mancini GB, Tashakkor AY, Baker S, Bergeron J, Fitchett D, Frohlich J, Genest J, Gupta M, Hegele RA, Ng DS, Pearson GJ, Pope J | title = Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Working Group Consensus update | journal = The Canadian Journal of Cardiology | volume = 29 | issue = 12 | pages = 1553–1568 | date = December 2013 | pmid = 24267801 | doi = 10.1016/j.cjca.2013.09.023 }}{{cite journal | vauthors = Richardson K, Schoen M, French B, Umscheid CA, Mitchell MD, Arnold SE, Heidenreich PA, Rader DJ, deGoma EM | title = Statins and cognitive function: a systematic review | journal = Annals of Internal Medicine | volume = 159 | issue = 10 | pages = 688–697 | date = November 2013 | pmid = 24247674 | doi = 10.7326/0003-4819-159-10-201311190-00007 | s2cid = 207536770 }}{{cite journal | vauthors = Smith DA | title = ACP Journal Club. Review: statins are not associated with cognitive impairment or dementia in cognitively intact adults | journal = Annals of Internal Medicine | volume = 160 | issue = 10 | pages = JC11, JC10 | date = May 2014 | pmid = 24842433 | doi = 10.7326/0003-4819-160-10-201405200-02011 | s2cid = 1990708 }}{{cite journal | vauthors = Bitzur R | title = Remembering Statins: Do Statins Have Adverse Cognitive Effects? | journal = Diabetes Care | volume = 39 | issue = Supplement 2 | pages = S253–S259 | date = August 2016 | pmid = 27440840 | doi = 10.2337/dcS15-3022 | type = Review | doi-access = free | title-link = doi }} A 2010 meta-review of medical trials involving over 65,000 people concluded that Statins decreased the risk of dementia, Alzheimer's disease, and even improved cognitive impairment in some cases.{{cite journal | vauthors = Ray KK, Seshasai SR, Erqou S, Sever P, Jukema JW, Ford I, Sattar N | title = Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants | journal = Archives of Internal Medicine | volume = 170 | issue = 12 | pages = 1024–1031 | date = June 2010 | pmid = 20585067 | doi = 10.1001/archinternmed.2010.182 | doi-access = free | title-link = doi }}{{Update inline|date=May 2019}} Additionally, both the Patient-Centered Research into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) study{{cite journal | vauthors = O'Brien EC, Greiner MA, Xian Y, Fonarow GC, Olson DM, Schwamm LH, Bhatt DL, Smith EE, Maisch L, Hannah D, Lindholm B, Peterson ED, Pencina MJ, Hernandez AF | title = Clinical Effectiveness of Statin Therapy After Ischemic Stroke: Primary Results From the Statin Therapeutic Area of the Patient-Centered Research Into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) Study | journal = Circulation | volume = 132 | issue = 15 | pages = 1404–1413 | date = October 2015 | pmid = 26246175 | doi = 10.1161/CIRCULATIONAHA.115.016183 | s2cid = 11252336 | doi-access = free | title-link = doi }} and the Health Protection Study (HPS) demonstrated that simvastatin and pravastatin did not affect cognition for patients with risk factors for, or a history of, vascular diseases.{{cite journal | vauthors = Mijajlović MD, Pavlović A, Brainin M, Heiss WD, Quinn TJ, Ihle-Hansen HB, Hermann DM, Assayag EB, Richard E, Thiel A, Kliper E, Shin YI, Kim YH, Choi S, Jung S, Lee YB, Sinanović O, Levine DA, Schlesinger I, Mead G, Milošević V, Leys D, Hagberg G, Ursin MH, Teuschl Y, Prokopenko S, Mozheyko E, Bezdenezhnykh A, Matz K, Aleksić V, Muresanu D, Korczyn AD, Bornstein NM | title = Post-stroke dementia - a comprehensive review | journal = BMC Medicine | volume = 15 | issue = 1 | pages = 11 | date = January 2017 | pmid = 28095900 | pmc = 5241961 | doi = 10.1186/s12916-017-0779-7 | doi-access = free | title-link = doi }}

There are reports of reversible cognitive impairment with statins.{{cite journal | vauthors = McDonagh J | title = Statin-related cognitive impairment in the real world: you'll live longer, but you might not like it | journal = JAMA Internal Medicine | volume = 174 | issue = 12 | pages = 1889 | date = December 2014 | pmid = 25347692 | doi = 10.1001/jamainternmed.2014.5376 }} The U.S. Food and Drug Administration (FDA) package insert on statins includes a warning about the potential for non-serious and reversible cognitive side effects with the medication (memory loss, confusion).{{Cite web|url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-important-safety-label-changes-cholesterol-lowering-statin-drugs|title=FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs|website=U.S. Food and Drug Administration (FDA)|date=19 January 2016|access-date=25 March 2018|archive-url=https://web.archive.org/web/20191013005904/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-important-safety-label-changes-cholesterol-lowering-statin-drugs|archive-date=13 October 2019|url-status=live}}

In observational studies 10–15% of people who take statins experience muscle problems; in most cases these consist of muscle pain. These rates, which are much higher than those seen in randomized clinical trials have been the topic of extensive debate and discussion.{{cite journal | vauthors = Backes JM, Ruisinger JF, Gibson CA, Moriarty PM | title = Statin-associated muscle symptoms-Managing the highly intolerant | journal = Journal of Clinical Lipidology | volume = 11 | issue = 1 | pages = 24–33 | date = January–February 2017 | pmid = 28391891 | doi = 10.1016/j.jacl.2017.01.006 }}

Muscle pain and other symptoms often cause patients to stop taking a statin.{{cite journal | vauthors = Yusuf S | title = Why do people not take life-saving medications? The case of statins | journal = Lancet | volume = 388 | issue = 10048 | pages = 943–945 | date = September 2016 | pmid = 27598664 | doi = 10.1016/s0140-6736(16)31532-x | s2cid = 34832961 }} This is known as statin intolerance. A 2021 double-blind multiple crossover randomized controlled trial (RCT) in statin-intolerant patients found that adverse effects, including muscle pain, were similar between atorvastatin and placebo.{{cite journal |vauthors=Herrett E, Williamson E, Brack K, Beaumont D, Perkins A, Thayne A, Shakur-Still H, Roberts I, Prowse D, Goldacre B, van Staa T, MacDonald TM, Armitage J, Wimborne J, Melrose P, Singh J, Brooks L, Moore M, Hoffman M, Smeeth L |date=February 2021 |title=Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials |journal=BMJ |volume=372 |pages=n135 |doi=10.1136/bmj.n135 |pmc=7903384 |pmid=33627334 |author21=StatinWISE Trial Group}} A smaller double-blind RCT obtained similar results.{{cite journal | vauthors = Wood FA, Howard JP, Finegold JA, Nowbar AN, Thompson DM, Arnold AD, Rajkumar CA, Connolly S, Cegla J, Stride C, Sever P, Norton C, Thom SA, Shun-Shin MJ, Francis DP | title = N-of-1 Trial of a Statin, Placebo, or No Treatment to Assess Side Effects | journal = The New England Journal of Medicine | volume = 383 | issue = 22 | pages = 2182–2184 | date = November 2020 | pmid = 33196154 | doi = 10.1056/NEJMc2031173 | hdl-access = free | s2cid = 226971988 | hdl = 10044/1/84185 }} The results of these studies help explain why statin symptom rates in observational studies are so much higher than in double-blind RCTs and support the notion that the difference results from the nocebo effect; that the symptoms are caused by expectations of harm.{{cite journal | vauthors = Colloca L, Barsky AJ | title = Placebo and Nocebo Effects | journal = The New England Journal of Medicine | volume = 382 | issue = 6 | pages = 554–561 | date = February 2020 | pmid = 32023375 | doi = 10.1056/NEJMra1907805 | s2cid = 211046068 }}

Media reporting on statins is often negative, and patient leaflets inform patients that rare but potentially serious muscle problems can occur during statin treatment. These create expectations of harm. Nocebo symptoms are real and bothersome and are a major barrier to treatment. Because of this, many people stop taking statins,{{cite journal | vauthors = Nelson AJ, Puri R, Nissen SE | title = Statins in a Distorted Mirror of Media | journal = Current Atherosclerosis Reports | volume = 22 | issue = 8 | pages = 37 | date = June 2020 | pmid = 32557172 | doi = 10.1007/s11883-020-00853-9 | s2cid = 219730531 }} which have been proven in numerous large-scale RCTs to reduce heart attacks, stroke, and deaths{{cite journal | vauthors = Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R | title = Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials | journal = Lancet | volume = 376 | issue = 9753 | pages = 1670–1681 | date = November 2010 | pmid = 21067804 | pmc = 2988224 | doi = 10.1016/S0140-6736(10)61350-5 }} – as long as people continue to take them.

Serious muscle problems such as rhabdomyolysis (destruction of muscle cells) and statin-associated autoimmune myopathy occur in less than 0.1% of treated people.{{cite journal | vauthors = Newman CB, Preiss D, Tobert JA, Jacobson TA, Page RL, Goldstein LB, Chin C, Tannock LR, Miller M, Raghuveer G, Duell PB, Brinton EA, Pollak A, Braun LT, Welty FK | title = Statin Safety and Associated Adverse Events: A Scientific Statement From the American Heart Association | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 39 | issue = 2 | pages = e38–e81 | date = February 2019 | pmid = 30580575 | doi = 10.1161/ATV.0000000000000073 | doi-access = free | title-link = doi }} Rhabdomyolysis can in turn result in life-threatening kidney injury. The risk of statin-induced rhabdomyolysis increases with older age, use of interacting medications such as fibrates, and hypothyroidism.{{cite web |url=http://www.patient.co.uk/doctor/rhabdomyolysis-and-other-causes-of-myoglobinuria |title=Rhabdomyolysis and Other Causes of Myoglobinuria |vauthors=Rull R, Henderson R |date=20 January 2015 |access-date=6 May 2015 |archive-date=7 May 2015 |archive-url=https://web.archive.org/web/20150507043157/http://www.patient.co.uk/doctor/rhabdomyolysis-and-other-causes-of-myoglobinuria |url-status=dead }}{{cite journal | vauthors = Mendes P, Robles PG, Mathur S | title = Statin-induced rhabdomyolysis: a comprehensive review of case reports | journal = Physiotherapy Canada. Physiotherapie Canada | volume = 66 | issue = 2 | pages = 124–132 | date = 2014 | pmid = 24799748 | pmc = 4006404 | doi = 10.3138/ptc.2012-65 }} Coenzyme Q10 (ubiquinone) levels are decreased in statin use;{{cite journal | vauthors = Potgieter M, Pretorius E, Pepper MS | title = Primary and secondary coenzyme Q10 deficiency: the role of therapeutic supplementation | journal = Nutrition Reviews | volume = 71 | issue = 3 | pages = 180–188 | date = March 2013 | pmid = 23452285 | doi = 10.1111/nure.12011 | doi-access = free | title-link = doi }} CoQ10 supplements are sometimes used to treat statin-associated myopathy, though evidence of their efficacy is lacking {{As of|2017|lc=on}}.{{cite journal | vauthors = Tan JT, Barry AR | title = Coenzyme Q10 supplementation in the management of statin-associated myalgia | journal = American Journal of Health-System Pharmacy | volume = 74 | issue = 11 | pages = 786–793 | date = June 2017 | pmid = 28546301 | doi = 10.2146/ajhp160714 | s2cid = 3825396 | doi-access = free | title-link = doi }} The gene SLCO1B1 (Solute carrier organic anion transporter family member 1B1) codes for an organic anion-transporting polypeptide that is involved in the regulation of the absorption of statins. A common variation in this gene was found in 2008 to significantly increase the risk of myopathy.{{cite journal | vauthors = Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, Gut I, Lathrop M, Collins R | title = SLCO1B1 variants and statin-induced myopathy--a genomewide study | journal = The New England Journal of Medicine | volume = 359 | issue = 8 | pages = 789–799 | date = August 2008 | pmid = 18650507 | doi = 10.1056/NEJMoa0801936 | author-link9 = Rory Collins | doi-access = free | title-link = doi }}

Records exist of over 250,000 people treated from 1998 to 2001 with the statin drugs atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin.{{cite journal | vauthors = Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L, Gurwitz JH, Chan KA, Goodman MJ, Platt R | title = Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs | journal = JAMA | volume = 292 | issue = 21 | pages = 2585–2590 | date = December 2004 | pmid = 15572716 | doi = 10.1001/jama.292.21.2585 | doi-access = free | title-link = doi }} The incidence of rhabdomyolysis was 0.44 per 10,000 patients treated with statins other than cerivastatin. However, the risk was over 10-fold greater if cerivastatin was used, or if the standard statins (atorvastatin, fluvastatin, lovastatin, pravastatin, or simvastatin) were combined with a fibrate (fenofibrate or gemfibrozil) treatment. Cerivastatin was withdrawn by its manufacturer in 2001.{{cite journal | vauthors = Backman JT, Filppula AM, Niemi M, Neuvonen PJ | title = Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions | journal = Pharmacological Reviews | volume = 68 | issue = 1 | pages = 168–241 | date = January 2016 | pmid = 26721703 | doi = 10.1124/pr.115.011411 | type = Review | doi-access = free | title-link = doi }}

Some researchers have suggested hydrophilic statins, such as fluvastatin, rosuvastatin, and pravastatin, are less toxic than lipophilic statins, such as atorvastatin, lovastatin, and simvastatin, but other studies have not found a connection. Lovastatin induces the expression of gene atrogin-1, which is believed to be responsible in promoting muscle fiber damage.{{cite journal | vauthors = Hanai J, Cao P, Tanksale P, Imamura S, Koshimizu E, Zhao J, Kishi S, Yamashita M, Phillips PS, Sukhatme VP, Lecker SH | title = The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity | journal = The Journal of Clinical Investigation | volume = 117 | issue = 12 | pages = 3940–3951 | date = December 2007 | pmid = 17992259 | pmc = 2066198 | doi = 10.1172/JCI32741 }} Tendon rupture does not appear to occur.{{cite journal | vauthors = Teichtahl AJ, Brady SR, Urquhart DM, Wluka AE, Wang Y, Shaw JE, Cicuttini FM | title = Statins and tendinopathy: a systematic review | journal = The Medical Journal of Australia | volume = 204 | issue = 3 | pages = 115–21.e1 | date = February 2016 | pmid = 26866552 | doi = 10.5694/mja15.00806 | s2cid = 4652858 }}

The relationship between statin use and risk of developing diabetes remains unclear and the results of reviews are mixed.{{cite journal | vauthors = Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SR, McMurray JJ, Freeman DJ, Jukema JW, Macfarlane PW, Packard CJ, Stott DJ, Westendorp RG, Shepherd J, Davis BR, Pressel SL, Marchioli R, Marfisi RM, Maggioni AP, Tavazzi L, Tognoni G, Kjekshus J, Pedersen TR, Cook TJ, Gotto AM, Clearfield MB, Downs JR, Nakamura H, Ohashi Y, Mizuno K, Ray KK, Ford I | title = Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials | journal = Lancet | volume = 375 | issue = 9716 | pages = 735–742 | date = February 2010 | pmid = 20167359 | doi = 10.1016/S0140-6736(09)61965-6 | s2cid = 11544414 }}{{cite journal | vauthors = Chou R, Dana T, Blazina I, Daeges M, Jeanne TL | title = Statins for Prevention of Cardiovascular Disease in Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force | journal = JAMA | volume = 316 | issue = 19 | pages = 2008–2024 | date = November 2016 | pmid = 27838722 | doi = 10.1001/jama.2015.15629 | type = Review | doi-access = free | title-link = doi }}{{cite journal | vauthors = Rochlani Y, Kattoor AJ, Pothineni NV, Palagiri RD, Romeo F, Mehta JL | title = Balancing Primary Prevention and Statin-Induced Diabetes Mellitus Prevention | journal = The American Journal of Cardiology | volume = 120 | issue = 7 | pages = 1122–1128 | date = October 2017 | pmid = 28797470 | doi = 10.1016/j.amjcard.2017.06.054 | type = Review | bibcode = 1981AmJC...48..728H }}{{cite journal | vauthors = He Y, Li X, Gasevic D, Brunt E, McLachlan F, Millenson M, Timofeeva M, Ioannidis JP, Campbell H, Theodoratou E | title = Statins and Multiple Noncardiovascular Outcomes: Umbrella Review of Meta-analyses of Observational Studies and Randomized Controlled Trials | journal = Annals of Internal Medicine | volume = 169 | issue = 8 | pages = 543–553 | date = October 2018 | pmid = 30304368 | doi = 10.7326/M18-0808 | s2cid = 52953760 }} Higher doses have a greater effect, but the decrease in cardiovascular disease outweighs the risk of developing diabetes.{{cite journal | vauthors = Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, DeMicco DA, Barter P, Cannon CP, Sabatine MS, Braunwald E, Kastelein JJ, de Lemos JA, Blazing MA, Pedersen TR, Tikkanen MJ, Sattar N, Ray KK | title = Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis | journal = JAMA | volume = 305 | issue = 24 | pages = 2556–2564 | date = June 2011 | pmid = 21693744 | doi = 10.1001/jama.2011.860 | doi-access = free | title-link = doi | hdl = 10044/1/39305 | hdl-access = free }} Use in postmenopausal women is associated with an increased risk for diabetes.{{cite journal | vauthors = Culver AL, Ockene IS, Balasubramanian R, Olendzki BC, Sepavich DM, Wactawski-Wende J, Manson JE, Qiao Y, Liu S, Merriam PA, Rahilly-Tierny C, Thomas F, Berger JS, Ockene JK, Curb JD, Ma Y | title = Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative | journal = Archives of Internal Medicine | volume = 172 | issue = 2 | pages = 144–152 | date = January 2012 | pmid = 22231607 | doi = 10.1001/archinternmed.2011.625 | doi-access = free | title-link = doi }} The exact mechanism responsible for the possible increased risk of diabetes mellitus associated with statin use is unclear. However, recent findings have indicated the inhibition of HMGCoAR as a key mechanism.{{cite journal | vauthors = Carmena R, Betteridge DJ | title = Diabetogenic Action of Statins: Mechanisms | journal = Current Atherosclerosis Reports | volume = 21 | issue = 6 | pages = 23 | date = April 2019 | pmid = 31037345 | doi = 10.1007/s11883-019-0780-z | s2cid = 140506916 }} Statins are thought to decrease cells' uptake of glucose from the bloodstream in response to the hormone insulin. One way this is thought to occur is by interfering with cholesterol synthesis which is necessary for the production of certain proteins responsible for glucose uptake into cells such as GLUT1.

Several meta-analyses have found no increased risk of cancer, and some meta-analyses have found a reduced risk.{{cite journal | vauthors = Jukema JW, Cannon CP, de Craen AJ, Westendorp RG, Trompet S | title = The controversies of statin therapy: weighing the evidence | journal = Journal of the American College of Cardiology | volume = 60 | issue = 10 | pages = 875–881 | date = September 2012 | pmid = 22902202 | doi = 10.1016/j.jacc.2012.07.007 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Rutishauser J | title = Statins in clinical medicine | journal = Swiss Medical Weekly | volume = 141 | pages = w13310 | date = 21 November 2011 | pmid = 22101921 | doi = 10.4414/smw.2011.13310 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Alsheikh-Ali AA, Maddukuri PV, Han H, Karas RH | title = Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials | journal = Journal of the American College of Cardiology | volume = 50 | issue = 5 | pages = 409–418 | date = July 2007 | pmid = 17662392 | doi = 10.1016/j.jacc.2007.02.073 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Dale KM, Coleman CI, Henyan NN, Kluger J, White CM | title = Statins and cancer risk: a meta-analysis | journal = JAMA | volume = 295 | issue = 1 | pages = 74–80 | date = January 2006 | pmid = 16391219 | doi = 10.1001/jama.295.1.74 }}{{cite journal | vauthors = Alsheikh-Ali AA, Karas RH | title = The relationship of statins to rhabdomyolysis, malignancy, and hepatic toxicity: evidence from clinical trials | journal = Current Atherosclerosis Reports | volume = 11 | issue = 2 | pages = 100–104 | date = March 2009 | pmid = 19228482 | doi = 10.1007/s11883-009-0016-8 | s2cid = 42869773 }} Specifically, statins may reduce the risk of esophageal cancer,{{cite journal | vauthors = Singh S, Singh AG, Singh PP, Murad MH, Iyer PG | title = Statins are associated with reduced risk of esophageal cancer, particularly in patients with Barrett's esophagus: a systematic review and meta-analysis | journal = Clinical Gastroenterology and Hepatology | volume = 11 | issue = 6 | pages = 620–629 | date = June 2013 | pmid = 23357487 | pmc = 3660516 | doi = 10.1016/j.cgh.2012.12.036 }} colorectal cancer,{{cite journal | vauthors = Liu Y, Tang W, Wang J, Xie L, Li T, He Y, Deng Y, Peng Q, Li S, Qin X | title = Association between statin use and colorectal cancer risk: a meta-analysis of 42 studies | journal = Cancer Causes & Control | volume = 25 | issue = 2 | pages = 237–249 | date = February 2014 | pmid = 24265089 | doi = 10.1007/s10552-013-0326-6 | s2cid = 17931279 }} gastric cancer,{{cite journal | vauthors = Wu XD, Zeng K, Xue FQ, Chen JH, Chen YQ | title = Statins are associated with reduced risk of gastric cancer: a meta-analysis | journal = European Journal of Clinical Pharmacology | volume = 69 | issue = 10 | pages = 1855–1860 | date = October 2013 | pmid = 23748751 | doi = 10.1007/s00228-013-1547-z | s2cid = 16584300 }}{{cite journal | vauthors = Singh PP, Singh S | title = Statins are associated with reduced risk of gastric cancer: a systematic review and meta-analysis | journal = Annals of Oncology | volume = 24 | issue = 7 | pages = 1721–1730 | date = July 2013 | pmid = 23599253 | doi = 10.1093/annonc/mdt150 | doi-access = free | title-link = doi }} hepatocellular carcinoma,{{cite journal | vauthors = Pradelli D, Soranna D, Scotti L, Zambon A, Catapano A, Mancia G, La Vecchia C, Corrao G | title = Statins and primary liver cancer: a meta-analysis of observational studies | journal = European Journal of Cancer Prevention | volume = 22 | issue = 3 | pages = 229–234 | date = May 2013 | pmid = 23010949 | doi = 10.1097/cej.0b013e328358761a | s2cid = 37195287 }} and possibly prostate cancer.{{cite journal | vauthors = Zhang Y, Zang T | title = Association between statin usage and prostate cancer prevention: a refined meta-analysis based on literature from the years 2005-2010 | journal = Urologia Internationalis | volume = 90 | issue = 3 | pages = 259–262 | year = 2013 | pmid = 23052323 | doi = 10.1159/000341977 | s2cid = 22078921 }}{{cite journal | vauthors = Bansal D, Undela K, D'Cruz S, Schifano F | title = Statin use and risk of prostate cancer: a meta-analysis of observational studies | journal = PLOS ONE | volume = 7 | issue = 10 | pages = e46691 | year = 2012 | pmid = 23049713 | pmc = 3462187 | doi = 10.1371/journal.pone.0046691 | bibcode = 2012PLoSO...746691B | doi-access = free | title-link = doi }} They appear to have no effect on the risk of lung cancer,{{cite journal | vauthors = Tan M, Song X, Zhang G, Peng A, Li X, Li M, Liu Y, Wang C | title = Statins and the risk of lung cancer: a meta-analysis | journal = PLOS ONE | volume = 8 | issue = 2 | pages = e57349 | year = 2013 | pmid = 23468972 | pmc = 3585354 | doi = 10.1371/journal.pone.0057349 | bibcode = 2013PLoSO...857349T | doi-access = free | title-link = doi }} kidney cancer,{{cite journal | vauthors = Zhang XL, Liu M, Qian J, Zheng JH, Zhang XP, Guo CC, Geng J, Peng B, Che JP, Wu Y | title = Statin use and risk of kidney cancer: a meta-analysis of observational studies and randomized trials | journal = British Journal of Clinical Pharmacology | volume = 77 | issue = 3 | pages = 458–465 | date = March 2014 | pmid = 23879311 | pmc = 3952720 | doi = 10.1111/bcp.12210 }} breast cancer,{{cite journal | vauthors = Undela K, Srikanth V, Bansal D | title = Statin use and risk of breast cancer: a meta-analysis of observational studies | journal = Breast Cancer Research and Treatment | volume = 135 | issue = 1 | pages = 261–269 | date = August 2012 | pmid = 22806241 | doi = 10.1007/s10549-012-2154-x | s2cid = 35249884 }} pancreatic cancer,{{cite journal | vauthors = Cui X, Xie Y, Chen M, Li J, Liao X, Shen J, Shi M, Li W, Zheng H, Jiang B | title = Statin use and risk of pancreatic cancer: a meta-analysis | journal = Cancer Causes & Control | volume = 23 | issue = 7 | pages = 1099–1111 | date = July 2012 | pmid = 22562222 | doi = 10.1007/s10552-012-9979-9 | s2cid = 13171692 }} or bladder cancer.{{cite journal | vauthors = Zhang XL, Geng J, Zhang XP, Peng B, Che JP, Yan Y, Wang GC, Xia SQ, Wu Y, Zheng JH | title = Statin use and risk of bladder cancer: a meta-analysis | journal = Cancer Causes & Control | volume = 24 | issue = 4 | pages = 769–776 | date = April 2013 | pmid = 23361339 | doi = 10.1007/s10552-013-0159-3 | s2cid = 9030195 }}

Combining any statin with a fibrate or niacin (other categories of lipid-lowering drugs) increases the risks for rhabdomyolysis to almost 6.0 per 10,000 persons, per year. Monitoring liver enzymes and creatine kinase is especially prudent in those on high-dose statins or in those on statin/fibrate combinations, and mandatory in the case of muscle cramps or of deterioration in kidney function.{{Cite journal |last1=Newman |first1=Connie B. |last2=Preiss |first2=David |last3=Tobert |first3=Jonathan A. |last4=Jacobson |first4=Terry A. |last5=Page |first5=Robert L. |last6=Goldstein |first6=Larry B. |last7=Chin |first7=Clifford |last8=Tannock |first8=Lisa R. |last9=Miller |first9=Michael |last10=Raghuveer |first10=Geetha |last11=Duell |first11=P. Barton |last12=Brinton |first12=Eliot A. |last13=Pollak |first13=Amy |last14=Braun |first14=Lynne T. |last15=Welty |first15=Francine K. |year=2019 |title=Statin Safety and Associated Adverse Events: A Scientific Statement From the American Heart Association |url=https://www.ahajournals.org/doi/10.1161/ATV.0000000000000073 |journal=Arteriosclerosis, Thrombosis, and Vascular Biology |volume=39 |issue=2 |pages=e38–e81 |doi=10.1161/ATV.0000000000000073 |issn=1079-5642 |pmid=30580575 |access-date=14 May 2024 |archive-date=28 May 2024 |archive-url=https://web.archive.org/web/20240528015624/https://www.ahajournals.org/doi/10.1161/ATV.0000000000000073 |url-status=live }}

Consumption of grapefruit or grapefruit juice inhibits the metabolism of certain statins, and bitter oranges may have a similar effect.[http://www.mayoclinic.com/health/food-and-nutrition/AN00413 Katherine Zeratsky, R.D., L.D., Mayo clinic: article on interference between grapefruit and medication] {{Webarchive|url=https://web.archive.org/web/20131029220210/http://www.mayoclinic.com/health/food-and-nutrition/AN00413 |date=29 October 2013 }} Accessed 1 May 2017 Furanocoumarins in grapefruit juice (i.e. bergamottin and dihydroxybergamottin) 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{{cite journal | vauthors = Kane GC, Lipsky JJ | title = Drug-grapefruit juice interactions | journal = Mayo Clinic Proceedings | volume = 75 | issue = 9 | pages = 933–942 | date = September 2000 | pmid = 10994829 | doi = 10.4065/75.9.933 | doi-access = free | title-link = doi }} (flavonoids (i.e. naringin) were thought to be responsible). This increases the levels of the statin, increasing the risk of dose-related adverse effects (including myopathy/rhabdomyolysis). The absolute prohibition of grapefruit juice consumption for users of some statins is controversial.{{cite journal | vauthors = Reamy BV, Stephens MB | title = The grapefruit-drug interaction debate: role of statins | journal = American Family Physician | volume = 76 | issue = 2 | pages = 190, 192; author reply 192 | date = July 2007 | pmid = 17695563 | url = http://www.aafp.org/afp/2007/0715/p190.html | access-date = 29 April 2012 | archive-date = 10 November 2018 | archive-url = https://web.archive.org/web/20181110120130/https://www.aafp.org/afp/2007/0715/p190.html | url-status = live }}

The U.S. Food and Drug Administration (FDA) notified healthcare professionals of updates to the prescribing information concerning interactions between protease inhibitors and certain statin drugs. Protease inhibitors and statins taken together may increase the blood levels of statins and increase the risk for muscle injury (myopathy). The most serious form of myopathy, rhabdomyolysis, can damage the kidneys and lead to kidney failure, which can be fatal.{{cite web | title=Statins and HIV or Hepatitis C Drugs: Drug Safety Communication – Interaction Increases Risk of Muscle Injury | website=U.S. Food and Drug Administration (FDA) | date=1 March 2012 | url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm294294.htm | archive-url=https://web.archive.org/web/20170118091759/https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm294294.htm | archive-date=18 January 2017 | access-date=12 October 2019}}

Studies have found that the use of statins may protect against getting osteoporosis and fractures or may induce osteoporosis and fractures.{{cite journal | vauthors = Lin TK, Chou P, Lin CH, Hung YJ, Jong GP | title = Long-term effect of statins on the risk of new-onset osteoporosis: A nationwide population-based cohort study | journal = PLOS ONE | volume = 13 | issue = 5 | pages = e0196713 | date = 2018 | pmid = 29723231 | pmc = 5933736 | doi = 10.1371/journal.pone.0196713 | doi-access = free | title-link = doi | bibcode = 2018PLoSO..1396713L }}{{cite journal | vauthors = Wang Z, Li Y, Zhou F, Piao Z, Hao J | title = Effects of Statins on Bone Mineral Density and Fracture Risk: A PRISMA-compliant Systematic Review and Meta-Analysis | journal = Medicine | volume = 95 | issue = 22 | pages = e3042 | date = May 2016 | pmid = 27258488 | pmc = 4900696 | doi = 10.1097/MD.0000000000003042 }}{{cite journal | vauthors = An T, Hao J, Sun S, Li R, Yang M, Cheng G, Zou M | title = Efficacy of statins for osteoporosis: a systematic review and meta-analysis | journal = Osteoporosis International | volume = 28 | issue = 1 | pages = 47–57 | date = January 2017 | pmid = 27888285 | doi = 10.1007/s00198-016-3844-8 | s2cid = 4723680 }}{{cite journal | vauthors = Larsson BA, Sundh D, Mellström D, Axelsson KF, Nilsson AG, Lorentzon M | title = Association Between Cortical Bone Microstructure and Statin Use in Older Women | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 104 | issue = 2 | pages = 250–257 | date = February 2019 | pmid = 30423123 | doi = 10.1210/jc.2018-02054 | doi-access = free | title-link = doi }} A cross-sectional retrospective analysis of the entire Austrian population found that the risk of getting osteoporosis is dependent on the dose used.{{cite journal | vauthors = Leutner M, Matzhold C, Bellach L, Deischinger C, Harreiter J, Thurner S, Klimek P, Kautzky-Willer A | title = Diagnosis of osteoporosis in statin-treated patients is dose-dependent | journal = Annals of the Rheumatic Diseases | volume = 78 | issue = 12 | pages = 1706–1711 | date = December 2019 | pmid = 31558481 | pmc = 6900255 | doi = 10.1136/annrheumdis-2019-215714 }}

{{Main|Cholesterol#Homeostasis}}

File:Atorvastatin binding.png entry {{PDBe|1hwk}}{{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 }}]]

File:HMG-CoA reductase pathway.svg.]]

Statins act by 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 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.{{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 }}

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,{{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 }} so statins with short 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,{{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 }}{{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 }} but have shown no difference in the long-acting atorvastatin.{{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 }}

In rabbits, liver cells sense the reduced levels of liver cholesterol and seek to compensate by synthesizing LDL receptors to draw cholesterol out of the circulation.{{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 }} This is accomplished via proteases that cleave membrane-bound sterol regulatory element binding proteins, which then migrate to the 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 LDL and 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}}

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 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 pleiotropic cardiovascular benefits of statins,{{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 }}{{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 }}{{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 }}{{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 }}{{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 }}{{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 }} 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,{{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 }} and may also account for some of the benefits seen in cancer reduction with statins.{{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 }} 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){{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 }} and elevated blood sugar (diabetes).{{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 }}

As noted above, statins exhibit action beyond lipid-lowering activity in the prevention of atherosclerosis through so-called "pleiotropic effects of statins". The pleiotropic effects of statins remain controversial.{{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 }} The ASTEROID trial showed direct ultrasound evidence of atheroma regression during statin therapy.{{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 }} Researchers hypothesize that statins prevent cardiovascular disease via four proposed mechanisms (all subjects of a large body of biomedical research):

1. Improve endothelial function
2. Modulate inflammatory responses
3. Maintain plaque stability
4. Prevent blood clot formation

In 2008, the JUPITER trial showed statins provided benefit in those who had no history of high cholesterol or heart disease, but only in those with elevated high-sensitivity C-reactive protein (hsCRP) levels, an indicator for inflammation.{{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 }} The study has been criticized due to perceived flaws in the study design,{{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 }}{{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 }}{{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 }} although Paul M. Ridker, lead investigator of the JUPITER trial, has responded to these criticisms at length.{{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 }}

{{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.{{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 }} 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.{{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 }}{{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 }}

The statins are divided into two groups: fermentation-derived and synthetic. Some specific types are listed in the table below. Note that the associated brand names may vary between countries.

LDL-lowering potency varies between agents. Cerivastatin is the most potent (withdrawn from the market in August 2001 due to risk of serious rhabdomyolysis), followed by (in order of decreasing potency) rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, and fluvastatin.{{cite journal | vauthors = Shepherd J, Hunninghake DB, Barter P, McKenney JM, Hutchinson HG | title = Guidelines for lowering lipids to reduce coronary artery disease risk: a comparison of rosuvastatin with atorvastatin, pravastatin, and simvastatin for achieving lipid-lowering goals | journal = The American Journal of Cardiology | volume = 91 | issue = 5A | pages = 11C–17C; discussion 17C–19C | date = March 2003 | pmid = 12646338 | doi = 10.1016/S0002-9149(03)00004-3 }} The relative potency of pitavastatin has not yet been fully established, but preliminary studies indicate a potency similar to rosuvastatin.{{cite journal | vauthors = Baldinelli L, Biselli R, Fattorossi A | title = Influence of ST 789 on murine thymocytes: a flow cytometry study of thymocyte subset distribution and of intracellular free Ca++ increase upon activation. Murine thymocytes and ST 789 | journal = Thymus | volume = 19 | issue = 2 Suppl 1 | pages = S53–S61 | date = February 2005 | pmid = 1585420 | doi = 10.1111/j.1742-1241.2005.00461.x | s2cid = 221814440 }}

Image:Pleurotus ostreatus JPG7.jpg, a culinary mushroom, naturally contains lovastatin.]]

Some types of statins are naturally occurring, and can be found in such foods as oyster mushrooms and red yeast rice. Randomized controlled trials have found these foodstuffs to reduce circulating cholesterol, but the quality of the trials has been judged to be low.{{cite journal | vauthors = Liu J, Zhang J, Shi Y, Grimsgaard S, Alraek T, Fønnebø V | title = Chinese red yeast rice (Monascus purpureus) for primary hyperlipidemia: a meta-analysis of randomized controlled trials | journal = Chinese Medicine | volume = 1 | issue = 1 | pages = 4 | date = November 2006 | pmid = 17302963 | pmc = 1761143 | doi = 10.1186/1749-8546-1-4 | doi-access = free | title-link = doi }}

Due to patent expiration, most of the block-buster branded statins have been generic since 2012, including atorvastatin, the largest-selling{{Cite journal |last1=Jackevicius |first1=Cynthia A. |last2=Chou |first2=Mindy M. |last3=Ross |first3=Joseph S. |last4=Shah |first4=Nilay D. |last5=Krumholz |first5=Harlan M. |date=19 January 2012 |title=Generic Atorvastatin and Health Care Costs |journal=New England Journal of Medicine |volume=366 |issue=3 |pages=201–204 |doi=10.1056/NEJMp1113112 |issn=0028-4793 |pmc=3319770 |pmid=22149736}} branded drug.{{cite web | vauthors = Fang J | title=Patent expires today on pharmaceutical superstar Lipitor | website=ZDNet | date=31 October 2019 | url=https://www.zdnet.com/article/patent-expires-today-on-pharmaceutical-superstar-lipitor/ | archive-url=https://web.archive.org/web/20191031085907/https://www.zdnet.com/article/patent-expires-today-on-pharmaceutical-superstar-lipitor/ | archive-date=31 October 2019 | url-status=live | access-date=31 October 2019 }}{{cite web | title=Sandoz launches authorized fluvastatin generic in US | website=GaBI Online | date=31 October 2019 | url=http://www.gabionline.net/Generics/News/Sandoz-launches-authorized-fluvastatin-generic-in-US | archive-url=https://web.archive.org/web/20191031090130/http://www.gabionline.net/Generics/News/Sandoz-launches-authorized-fluvastatin-generic-in-US | archive-date=31 October 2019 | url-status=live | access-date=31 October 2019}}{{cite press release | title=Teva Announces Final Approval of Lovastatin Tablets | website=Teva Pharmaceutical Industries Ltd. | date=31 October 2019 | url=https://www.tevapharm.com/news/teva_announces_final_approval_of_lovastatin_tablets_12_01.aspx | archive-url=https://web.archive.org/web/20191031090617/https://www.tevapharm.com/news/teva_announces_final_approval_of_lovastatin_tablets_12_01.aspx | archive-date=31 October 2019 | url-status=live | access-date=31 October 2019}}{{cite web | title=FDA OKs Generic Version of Pravachol | website=WebMD | date=25 April 2006 | url=https://www.webmd.com/cholesterol-management/news/20060425/fda-oks-generic-version-pravachol | access-date=31 October 2019 | archive-date=31 October 2019 | archive-url=https://web.archive.org/web/20191031090912/https://www.webmd.com/cholesterol-management/news/20060425/fda-oks-generic-version-pravachol | url-status=live }}{{cite news | title=Generic Crestor Wins Approval, Dealing a Blow to AstraZeneca | website=The New York Times | date=21 July 2016 | url=https://www.nytimes.com/2016/07/21/business/generic-crestor-wins-approval-dealing-a-blow-to-astrazeneca.html | access-date=31 October 2019 | archive-date=31 October 2019 | archive-url=https://web.archive.org/web/20191031092230/https://www.nytimes.com/2016/07/21/business/generic-crestor-wins-approval-dealing-a-blow-to-astrazeneca.html | url-status=live }}{{cite news | vauthors=Wilson D | title=Drug Firms Face Billions in Losses as Patents End | newspaper=The New York Times | date=6 March 2011 | url=https://www.nytimes.com/2011/03/07/business/07drug.html | access-date=31 October 2019 | archive-date=22 November 2019 | archive-url=https://web.archive.org/web/20191122014528/https://www.nytimes.com/2011/03/07/business/07drug.html | url-status=live }}{{cite news | vauthors=Berenson A | title=Merck Loses Protection for Patent on Zocor | newspaper=The New York Times | date=23 June 2006 | url=https://www.nytimes.com/2006/06/23/business/23statin.html | access-date=31 October 2019 | archive-date=14 January 2015 | archive-url=https://web.archive.org/web/20150114212534/http://www.nytimes.com/2006/06/23/business/23statin.html?_r=0 | url-status=live }}

{{notelist}}

{{Main|Statin development}}

The role of cholesterol in the development of cardiovascular disease was elucidated in the second half of the 20th century.{{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 }} This lipid hypothesis prompted attempts to reduce cardiovascular disease burden by lowering cholesterol. Treatment consisted mainly of 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.{{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}} 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.{{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 }}

In 1971, Akira Endo, a Japanese biochemist working for the pharmaceutical company 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. 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 (isoprenoids). 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.{{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 }} The British group mentions antifungal properties, with no mention of HMG-CoA reductase inhibition.{{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}}{{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}} 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.{{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 |volume=147 |issue=1 |pages=58–62, 66, 68 |pmid=12602122}}

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%.{{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 }} In 1995, Zocor and Mevacor both made Merck over {{US$|1 billion}}.

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.{{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 }} Endo was also inducted into the National Inventors Hall of Fame in Alexandria, Virginia in 2012. Michael S. Brown and 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."{{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 }}

{{as of|2016}} misleading claims exaggerating the adverse effects of statins had received widespread media coverage, with a consequent negative impact to public health. 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.{{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 }} An unintended effect of the academic statin controversy has been the spread of scientifically questionable 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..."{{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 }} promoting unproven medical therapies. Harriet Hall sees a spectrum of "statin denialism" ranging from pseudoscientific claims to the understatement of benefits and overstatement of side effects, all of which is contrary to the scientific evidence.{{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 }}

Several statins have been approved as generic drugs in the United States:

• Lovastatin (Mevacor) in December 2001{{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 }}{{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}}{{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 }}
• Pravastatin (Pravachol) in April 2006{{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 }}{{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=dead }}{{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 }}
• Simvastatin (Zocor) in June 2006{{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}}{{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}}{{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 }}
• Atorvastatin (Lipitor) in November 2011{{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 }}{{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 }}{{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 }}{{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 }}
• Fluvastatin (Lescol) in April 2012{{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}}{{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 }}
• Pitavastatin (Livalo) and rosuvastatin (Crestor) in 2016{{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 }}{{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=dead }}
• Ezetimibe/simvastatin (Vytorin) and ezetimibe/atorvastatin (Liptruzet) in 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=dead }}

Clinical studies have been conducted on the use of statins in dementia,{{cite journal | vauthors = Wolozin B, Wang SW, Li NC, Lee A, Lee TA, Kazis LE | title = Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease | journal = BMC Medicine | volume = 5 | issue = 1 | pages = 20 | date = July 2007 | pmid = 17640385 | pmc = 1955446 | doi = 10.1186/1741-7015-5-20 | doi-access = free | title-link = doi | author-link = Benjamin Wolozin }} lung cancer,{{cite journal | vauthors = Khurana V, Bejjanki HR, Caldito G, Owens MW | title = Statins reduce the risk of lung cancer in humans: a large case-control study of US veterans | journal = Chest | volume = 131 | issue = 5 | pages = 1282–1288 | date = May 2007 | pmid = 17494779 | doi = 10.1378/chest.06-0931 }} nuclear cataracts,{{cite journal | vauthors = Klein BE, Klein R, Lee KE, Grady LM | title = Statin use and incident nuclear cataract | journal = JAMA | volume = 295 | issue = 23 | pages = 2752–2758 | date = June 2006 | pmid = 16788130 | doi = 10.1001/jama.295.23.2752 | doi-access = free | title-link = doi }} hypertension,{{cite journal | vauthors = Golomb BA, Dimsdale JE, White HL, Ritchie JB, Criqui MH | title = Reduction in blood pressure with statins: results from the UCSD Statin Study, a randomized trial | journal = Archives of Internal Medicine | volume = 168 | issue = 7 | pages = 721–727 | date = April 2008 | pmid = 18413554 | pmc = 4285458 | doi = 10.1001/archinte.168.7.721 }}{{cite journal | vauthors = Drapala A, Sikora M, Ufnal M | title = Statins, the renin-angiotensin-aldosterone system and hypertension - a tale of another beneficial effect of statins | journal = Journal of the Renin-Angiotensin-Aldosterone System | volume = 15 | issue = 3 | pages = 250–258 | date = September 2014 | pmid = 25037529 | doi = 10.1177/1470320314531058 | doi-access = free | title-link = doi }} and prostate cancer{{cite journal | vauthors = Mondul AM, Han M, Humphreys EB, Meinhold CL, Walsh PC, Platz EA | title = Association of statin use with pathological tumor characteristics and prostate cancer recurrence after surgery | journal = The Journal of Urology | volume = 185 | issue = 4 | pages = 1268–1273 | date = April 2011 | pmid = 21334020 | pmc = 3584560 | doi = 10.1016/j.juro.2010.11.089 }} and breast cancer.{{cite journal | vauthors = Liu B, Yi Z, Guan X, Zeng YX, Ma F | title = The relationship between statins and breast cancer prognosis varies by statin type and exposure time: a meta-analysis | journal = Breast Cancer Research and Treatment | volume = 164 | issue = 1 | pages = 1–11 | date = July 2017 | pmid = 28432513 | doi = 10.1007/s10549-017-4246-0 | s2cid = 3900946 }} There is no high quality evidence that statins are useful for pneumonia.{{cite journal | vauthors = Batais MA, Khan AR, Bin Abdulhak AA | title = The Use of Statins and Risk of Community-Acquired Pneumonia | journal = Current Infectious Disease Reports | volume = 19 | issue = 8 | pages = 26 | date = August 2017 | pmid = 28639080 | doi = 10.1007/s11908-017-0581-x | s2cid = 20522253 }} The small number of available trials do not support the use of statins as an adjunctive therapy or as a monotherapy in multiple sclerosis.{{cite journal | vauthors = Wang J, Xiao Y, Luo M, Luo H | title = Statins for multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | volume = 2011 | issue = 12 | pages = CD008386 | date = December 2011 | pmid = 22161428 | pmc = 7175839 | doi = 10.1002/14651858.CD008386.pub3 }}

Statins show a effect in reducing depressive symptoms post-myocardial infarction when used alongside standard antidepressants, though they are not effective as standalone treatments.{{Cite journal |last1=Gutlapalli |first1=Sai Dheeraj |last2=Farhat |first2=Hadi |last3=Irfan |first3=Huma |last4=Muthiah |first4=Kanmani |last5=Pallipamu |first5=Namratha |last6=Taheri |first6=Sogand |last7=Thiagaraj |first7=Suvedha S. |last8=Shukla |first8=Twisha S. |last9=Giva |first9=Sheiniz |last10=Penumetcha |first10=Sai Sri |date=2022 |title=The Anti-Depressant Effects of Statins in Patients With Major Depression Post-Myocardial Infarction: An Updated Review 2022 |journal=Cureus |volume=14 |issue=12 |pages=e32323 |doi=10.7759/cureus.32323 |doi-access=free |issn=2168-8184 |pmc=9825119 |pmid=36628002}}

A modelling study in the UK found that people aged 70 and older who take statins live longer in good health than those who do not, regardless of whether they have cardiovascular disease.{{Cite journal |last1=Mihaylova |first1=Borislava |last2=Wu |first2=Runguo |last3=Zhou |first3=Junwen |last4=Williams |first4=Claire |last5=Schlackow |first5=Iryna |last6=Emberson |first6=Jonathan |last7=Reith |first7=Christina |last8=Keech |first8=Anthony |last9=Robson |first9=John |last10=Parnell |first10=Richard |last11=Armitage |first11=Jane |last12=Gray |first12=Alastair |last13=Simes |first13=John |last14=Baigent |first14=Colin |date=2024-11-01 |title=Lifetime effects and cost-effectiveness of statin therapy for older people in the United Kingdom: a modelling study |journal=Heart |language=en |volume=110 |issue=21 |pages=1277–1285 |doi=10.1136/heartjnl-2024-324052 |issn=1355-6037 |pmid=39256053|pmc=11503164 }}{{Cite journal |title=Older people who take statins live longer in better health |url=https://evidence.nihr.ac.uk/alert/older-people-who-take-statins-live-longer-in-better-health/ |access-date=22 January 2025 |website=NIHR Evidence|date=2025 |doi=10.3310/nihrevidence_65725 |doi-access=free }}

{{Reflist}}

• {{cite web | vauthors = Brody JE | title=Weighing the Pros and Cons of Statins | website=The New York Times | date=16 April 2018 | url=https://www.nytimes.com/2018/04/16/well/weighing-the-pros-and-cons-of-statins.html }}

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