Editing Statin (section)

==Adverse effects==
{| class="wikitable" style="float: right"
|+ Choosing a statin for people with special considerations<ref name="BBDstatins2">table adapted from the following source, but check individual references for technical explanations
* {{Citation |author1 = Consumer Reports |author1-link = Consumer Reports |author2 = Drug Effectiveness Review Project |author2-link = Drug Effectiveness Review Project |date = March 2013 |title = Evaluating statin drugs to treat High Cholesterol and Heart Disease: Comparing Effectiveness, Safety, and Price |publisher = Consumer Reports |work = Best Buy Drugs |page = 9 |url = http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/StatinsUpdate-FINAL.pdf |access-date = 27 March 2013 |archive-date = 4 February 2017 |archive-url = https://web.archive.org/web/20170204145318/http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/StatinsUpdate-FINAL.pdf |url-status = live }}</ref>
|-
! Condition
! Commonly recommended statins
! Explanation
|-
| [[Kidney transplantation]] recipients taking [[ciclosporin]]
| [[Pravastatin]] or [[fluvastatin]]
| Drug interactions are possible, but studies have not shown that these statins increase exposure to ciclosporin.<ref>{{cite journal | vauthors = Asberg A | title = Interactions between cyclosporin and lipid-lowering drugs: implications for organ transplant recipients | journal = Drugs | volume = 63 | issue = 4 | pages = 367–378 | year = 2003 | pmid = 12558459 | doi = 10.2165/00003495-200363040-00003 | s2cid = 46971444 }}</ref>
|-
|[[HIV-positive people]] taking [[Protease inhibitor (pharmacology)|protease inhibitors]]
|[[Atorvastatin]], [[pravastatin]] or [[fluvastatin]]
|Negative interactions are more likely with other choices.<ref>{{cite web |url= https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-interactions-between-certain-hiv-or-hepatitis-c-drugs-and-cholesterol |title=FDA Drug Safety Communication: Interactions between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury |work=U.S. [[Food and Drug Administration]] (FDA) |date=1 March 2012 |access-date=3 April 2013 |archive-url=https://web.archive.org/web/20130318182724/https://www.fda.gov/Drugs/DrugSafety/ucm293877.htm |archive-date=18 March 2013 |url-status=live}}</ref>
|-
|Persons taking [[gemfibrozil]], a non-statin lipid-lowering drug
|Atorvastatin
|Combining gemfibrozil and a statin increases risk of [[rhabdomyolysis]] and subsequently [[kidney failure]]<ref name=safety>{{cite journal | vauthors = Bellosta S, Paoletti R, Corsini A | title = Safety of statins: focus on clinical pharmacokinetics and drug interactions | journal = Circulation | volume = 109 | issue = 23 Suppl 1 | pages = III50–III57 | date = June 2004 | pmid = 15198967 | doi = 10.1161/01.CIR.0000131519.15067.1f | doi-access = free | title-link = doi | hdl = 2434/143653 | hdl-access = free }}</ref><ref>{{cite journal | vauthors = Omar MA, Wilson JP | title = FDA adverse event reports on statin-associated rhabdomyolysis | journal = The Annals of Pharmacotherapy | volume = 36 | issue = 2 | pages = 288–295 | date = February 2002 | pmid = 11847951 | doi = 10.1345/aph.1A289 | s2cid = 43757439 }}</ref>
|-
|Persons taking the [[anticoagulant]] [[warfarin]]
|Any statin
|The statin use may require that the warfarin dose be changed, as some statins increase the effect of warfarin.<ref>{{cite journal | vauthors = Armitage J | title = The safety of statins in clinical practice | journal = Lancet | volume = 370 | issue = 9601 | pages = 1781–1790 | date = November 2007 | pmid = 17559928 | doi = 10.1016/S0140-6736(07)60716-8 | s2cid = 205948651 }}</ref>
|}

The most important adverse side effects are muscle problems, an increased risk of [[diabetes mellitus]], and [[elevated transaminases|increased liver enzymes in the blood]] due to [[liver damage]].<ref name="Naci2013"/><ref name=Bellosta2012>{{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 }}</ref> 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.<ref name="Collins2016">{{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 }}</ref> 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 [[Coenzyme Q10|CoQ<sub>10</sub>]] production, which is important for muscle function and sugar regulation.<ref>{{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 }}</ref>

Other possible adverse effects include [[neuropathy]],<ref>{{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 }}</ref><ref>{{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 }}</ref> [[pancreas|pancreatic]] and [[liver]] dysfunction, and [[sexual dysfunction]].<ref name=GolombEvans2008/> 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.<ref>{{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 }}</ref><ref>{{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 }}</ref><ref>{{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 }}</ref> A [[Cochrane Library|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.<ref name="Cochrane13" /> 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.<ref>{{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 }}</ref> The author of one study argued that adverse events are more common in clinical practice than in [[randomized clinical trial]]s.<ref name=GolombEvans2008>{{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 }}</ref> 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).<ref name="Mancini GB, Baker S, Bergeron J, et al. 2011 635–62">{{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 }}</ref> 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.<ref>{{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 }}</ref>

===Cognitive effects===
Multiple systematic reviews and meta-analyses have concluded that the available evidence does not support an association between statin use and cognitive decline.<ref name="Swiger2013">{{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 }}</ref><ref>{{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 }}</ref><ref name="Richardson">{{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 }}</ref><ref name="Smith2014">{{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 }}</ref><ref name="Bitzur2016">{{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 }}</ref> 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.<ref>{{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 }}</ref>{{Update inline|date=May 2019}} Additionally, both the Patient-Centered Research into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) study<ref>{{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 }}</ref> 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.<ref>{{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 }}</ref>

There are reports of reversible cognitive impairment with statins.<ref name="McDonagh">{{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 }}</ref> 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).<ref>{{Cite web|url=https://www.fda.gov/Drugs/DrugSafety/ucm293101.htm|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}}</ref>

===Muscles===
In observational studies 10–15% of people who take statins experience [[skeletal striated muscle|muscle]] problems; in most cases these consist of [[myalgia|muscle pain]].<ref name=Jacob2011/> These rates, which are much higher than those seen in randomized clinical trials<ref name="Mancini GB, Baker S, Bergeron J, et al. 2011 635–62"/> have been the topic of extensive debate and discussion.<ref name="Collins2016" /><ref name="Backes2017">{{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 }}</ref>

Muscle pain and other symptoms often cause patients to stop taking a statin.<ref>{{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 }}</ref> This is known as statin intolerance. A 2021 double-blind [[N of 1 trial|multiple crossover]] [[randomized controlled trial]] (RCT) in statin-intolerant patients found that adverse effects, including muscle pain, were similar between atorvastatin and placebo.<ref>{{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}}</ref> A smaller double-blind RCT obtained similar results.<ref>{{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 }}</ref> 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|nocebo effect]]; that the symptoms are caused by expectations of harm.<ref>{{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 }}</ref>

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,<ref>{{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 }}</ref> which have been proven in numerous large-scale RCTs to reduce heart attacks, stroke, and deaths<ref>{{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 }}</ref> – 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.<ref>{{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 }}</ref> Rhabdomyolysis can in turn result in life-threatening [[acute tubular necrosis|kidney injury]]. The risk of statin-induced rhabdomyolysis increases with older age, use of interacting medications such as [[fibrates]], and [[hypothyroidism]].<ref>{{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 }}</ref><ref>{{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 }}</ref> [[Coenzyme Q10]] (ubiquinone) levels are decreased in statin use;<ref name="Potgieter2013">{{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 }}</ref> CoQ10 supplements are sometimes used to treat statin-associated myopathy, though evidence of their efficacy is lacking {{As of|2017|lc=on}}.<ref name="Tan2017">{{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 }}</ref> 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.<ref name="The SEARCH Collaborative Group">{{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 }}</ref>

Records exist of over 250,000 people treated from 1998 to 2001 with the statin drugs atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin.<ref name="Graham2004">{{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 }}</ref> 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.<ref name="Backman2016">{{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 }}</ref>

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.<ref name="Hanaietal2007"/> [[Lovastatin]] induces the expression of gene ''[[FBXO32|atrogin-1]]'', which is believed to be responsible in promoting muscle fiber damage.<ref name="Hanaietal2007">{{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 }}</ref> Tendon rupture does not appear to occur.<ref>{{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 }}</ref>

===Diabetes===
The relationship between statin use and risk of developing [[diabetes mellitus|diabetes]] remains unclear and the results of reviews are mixed.<ref name="pmid20167359">{{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 }}</ref><ref name="Chou2016">{{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 }}</ref><ref name="Rochlani2017">{{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 }}</ref><ref>{{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 }}</ref> Higher doses have a greater effect, but the decrease in cardiovascular disease outweighs the risk of developing diabetes.<ref name="pmid21693744">{{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 }}</ref> Use in postmenopausal women is associated with an increased risk for diabetes.<ref name="Culver 2012">{{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 }}</ref> The exact mechanism responsible for the possible increased risk of diabetes mellitus associated with statin use is unclear.<ref name="Rochlani2017"/> However, recent findings have indicated the inhibition of [[HMG-CoA reductase|HMGCoAR]] as a key mechanism.<ref>{{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 }}</ref> Statins are thought to decrease cells' uptake of glucose from the bloodstream in response to the [[hormone]] [[insulin]].<ref name="Rochlani2017"/> 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]].<ref name="Rochlani2017"/>

===Cancer===
Several meta-analyses have found no increased risk of cancer, and some meta-analyses have found a reduced risk.<ref>{{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 }}</ref><ref>{{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 }}</ref><ref>{{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 }}</ref><ref name="Dale2006">{{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 }}</ref><ref>{{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 }}</ref> Specifically, statins may reduce the risk of [[esophageal cancer]],<ref>{{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 }}</ref> [[colorectal cancer]],<ref>{{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 }}</ref> [[gastric cancer]],<ref>{{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 }}</ref><ref>{{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 }}</ref> [[hepatocellular carcinoma]],<ref>{{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 }}</ref> and possibly [[prostate cancer]].<ref>{{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 }}</ref><ref>{{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 }}</ref> They appear to have no effect on the risk of [[lung cancer]],<ref>{{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 }}</ref> [[kidney cancer]],<ref>{{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 }}</ref> [[breast cancer]],<ref>{{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 }}</ref> [[pancreatic cancer]],<ref>{{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 }}</ref> or [[bladder cancer]].<ref>{{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 }}</ref>

===Drug interactions===
Combining any statin with a [[fibrate]] or [[Niacin (substance)|niacin]] (other categories of lipid-lowering drugs) increases the risks for [[rhabdomyolysis]] to almost 6.0 per 10,000 persons, per year.<ref name="Graham2004"/> 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]].<ref>{{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 }}</ref>

Consumption of [[grapefruit]] or [[grapefruit juice]] [[Grapefruit–drug interactions|inhibits]] the metabolism of certain statins, and [[bitter orange]]s may have a similar effect.<ref>[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</ref> Furanocoumarins in grapefruit juice (i.e. [[bergamottin]] and [[6',7'-dihydroxybergamottin|dihydroxybergamottin]]) inhibit the [[Cytochrome P450 oxidase|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<ref name="Kane2000">{{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 }}</ref> (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.<ref name="pmid17695563">{{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 }}</ref>

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.<ref>{{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}}</ref>

===Osteoporosis and fractures===
Studies have found that the use of statins may protect against getting osteoporosis and fractures or may induce osteoporosis and fractures.<ref>{{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 }}</ref><ref>{{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 }}</ref><ref>{{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 }}</ref><ref>{{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 }}</ref> A cross-sectional retrospective analysis of the entire Austrian population found that the risk of getting osteoporosis is dependent on the dose used.<ref>{{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 }}</ref>