Statins (or HMG-CoA reductase inhibitors) are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver, which produces about 70 percent of total cholesterol in the body. High cholesterol levels have been associated with cardiovascular disease (CVD). Statins have been found to prevent cardiovascular disease in those who are at high risk. The evidence is strong that statins are effective for treating CVD in the early stages of a disease (secondary prevention). The evidence is weaker that statins are effective for those with elevated cholesterol levels but without CVD (primary prevention). Side effects of statins include muscle pain, increased risk of diabetes and abnormalities in liver enzyme tests. Additionally, they have rare but severe adverse effects, particularly muscle damage.
Clinical practice guidelines generally recommend people to try "lifestyle modification", including a cholesterol-lowering diet and physical exercise, before statin use; statins or other pharmacologic agents may be recommended for those who do not meet their lipid-lowering goals through diet and lifestyle changes.
Most evidence suggests that statins are 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. A 2011 review reached similar conclusions. And a 2012 review found benefits in both women and men. A 2010 review concluded that treating people with no history of cardiovascular disease reduces cardiovascular events in men but not women, and provides no mortality benefit in either sex. Two other meta analyses published that year, one of which used data obtained exclusively from women, found no mortality benefit in primary prevention.
Statins are effective in decreasing mortality in people with pre-existing CVD. They are also currently advocated for use in patients at high risk of developing heart disease. 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. They have less effect than the fibrates or niacin in reducing triglycerides and raising HDL-cholesterol ("good cholesterol").
While no direct comparison exists, all statins appear effective regardless of potency or degree of cholesterol reduction. There do appear to be some differences between them, with simvastatin and pravastatin appearing superior in terms of side-effects.
A comparison of atorvastatin, pravastatin and simvastatin, based on their effectiveness against placebos, found, at commonly prescribed doses, no statistically significant differences among agents in reducing cardiovascular morbidity and mortality.
In children statins are effective at reducing cholesterol levels in those with familial hypercholesterolemia. Their long term safety is; however, unclear. Some recommend that if lifestyle changes are not enough statins should be started at 8 years old.
Choosing a statin for people with special considerations
The statin use may require that the warfarin dose be changed, as some statins increase the effect of warfarin.
The most important adverse side effects are increased concentrations of liver enzymes, muscle problems, and an increased risk of diabetes. Other possible adverse effects include cognitive loss, neuropathy, pancreatic and hepatic 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. A Cochrane group 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. The author of one study argued that adverse events are more common in clinical practice than in randomized clinical trials. A systematic review by the Canadian Working Group Consensus Conference that considered published meta analyses of clinical trials, spontaneous adverse event reports to the FDA, and published cohort studies 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 patient years). A systematic review co-authored by Ben Goldacre concluded that only a small fraction of side effects reported by patients on statins are actually attributable to the statin.
Two randomized clinical trials found cognitive issues, while two did not; recurrence upon reintroduction suggests these are causally related to statins in some individuals. A systematic review by the Canadian Working Group Consensus Conference concluded that "the available evidence is not strongly supportive of a major adverse effect of statins".
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.
Rare reactions include myopathies such as myositis (inflammation of the muscles) or even rhabdomyolysis (destruction of muscle cells), which can in turn result in life-threatening kidney injury. Coenzyme Q10 (ubiquinone) levels are decreased in statin use; CoQ10 supplements are sometimes used to treat statin-associated myopathy, though evidence of their efficacy is lacking as of 2007[update]. 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.
Graham et al. (2004) reviewed records of over 250,000 patients treated from 1998 to 2001 with the statin drugs atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin. The incidence of rhabdomyolyis 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 fibrate (fenofibrate or gemfibrozil) treatment. Cerivastatin was withdrawn by its manufacturer in 2001.
All commonly used statins show somewhat similar results, but the newer statins, characterized by longer pharmacological half-lives and more cellular specificity, have had a better ratio of efficacy to lower adverse effect rates. 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; the risk of myopathy was suggested to be lowest with pravastatin and fluvastatin, probably because they are more hydrophilic and as a result have less muscle penetration.Lovastatin induces the expression of gene atrogin-1, which is believed to be responsible in promoting muscle fiber damage.
Statins may increase the risk of diabetes by 9%, with higher doses appearing to have a larger effect.
Statins do not appear to be associated with cancer. Although there have been concerns that they might increase risk, several meta-analyses have found no relationship.
Combining any statin with a fibrate or niacin, another category of lipid-lowering drugs, increases the risks for rhabdomyolysis to almost 6.0 per 10,000 person-years. Most physicians have now abandoned routine monitoring of liver enzymes and creatine kinase, although they still consider this 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 renal function.
Consumption of grapefruit or grapefruit juice inhibits the metabolism of certain statins. Bitter oranges may have a similar effect. 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 (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.
The 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.
Mechanism of action
Atorvastatin bound to HMG-CoA reductase: PDB entry 1hwk
The HMG-CoA reductase pathway, which is blocked by statins via inhibiting the rate limiting enzyme HMG-CoA reductase.
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, 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, but have shown no difference in the long-acting atorvastatin.
Increasing LDL uptake
In rabbits, hepatocytes (liver cells) sense the reduced levels of liver cholesterol and seek to compensate by synthesizing LDL receptors to draw cholesterol out of the circulation. This is accomplished via protease enzymes that cleave a protein called "membrane-bound sterol regulatory element binding protein", which migrates to the nucleus and causes increased production of various other proteins and enzymes, including the LDL receptor. The LDL receptor then relocates to the liver cell membrane and binds to passing LDL and VLDL particles (the "bad cholesterol" linked to disease). LDL and VLDL are drawn out of circulation into the liver, where the cholesterol is reprocessed into bile salts. These are excreted, and subsequently recycled mostly by an internal bile salt circulation.
Decreasing of specific protein prenylation
Statins, by inhibiting the HMG CoA reductase pathway, simultaneously inhibit the production of both cholesterol and specific prenylated proteins (see diagram). A 2012 study found that statin treatment increases lifespan and improves cardiac health in Drosophila by decreasing specific protein prenylation. The study concluded, "These data are the most direct evidence to date that decreased protein prenylation can increase cardiac health and lifespan in any metazoan [animal] species, and may explain the pleiotropic (non-cholesterol related) health effects of statins." This inhibitory effect on protein prenylation may be involved, at least partially, in the improvement of endothelial function and other pleiotropic cardiovascular benefits of statins, and may also account for certain of the benefits seen in cancer reduction with statins.
There is controversy that statins may benefit those without high cholesterol. In 2008, the JUPITER study showed benefit in those who had no history of high cholesterol or heart disease, but only elevated C-reactive protein levels. An independent review did not consider the results of the trial to support these conclusions and raised concern of bias due to funding from the manufacturer.
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
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. The relative potency of pitavastatin has not yet been fully established.
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. Due to patent expiration, most of the block-buster branded statins have been generic since 2012, including atorvastatin, the largest-selling branded drug.
Statin equivalent dosages
% LDL reduction (approx.)
* 80-mg dose no longer recommended due to increased risk of rhabdomyolysis
In 1971, Akira Endo, a Japanese biochemist working for the pharmaceutical company Sankyo, began the search for a cholesterol-lowering drug. Research had already shown cholesterol is mostly manufactured by the body in the liver, using 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 (ergosterol) or cytoskeleton (isoprenoids). The first agent they identified was mevastatin (ML-236B), a molecule produced by the fungus Penicillium citrinum.
A British group isolated the same compound from Penicillium brevicompactum, named it compactin, and published their report in 1976. The British group mentions antifungal properties, with no mention of HMG-CoA reductase inhibition.
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.
A link between cholesterol and cardiovascular disease, known as the lipid hypothesis, had already been suggested. Cholesterol is the main constituent of atheroma, the fatty lumps in the wall of arteries that occur in atherosclerosis and, when ruptured, cause the vast majority of heart attacks. 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.
To market statins effectively, Merck had to convince the public of the dangers of high cholesterol, and doctors that statins were safe and would extend lives. As a result of public campaigns, people in the United States became familiar with their cholesterol numbers and the difference between "good" and "bad" cholesterol, and rival 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%. In 1995, Zocor and Mevacor both made Merck over US$1 billion. Endo was awarded the 2006 Japan Prize, and the Lasker-DeBakey Clinical Medical Research Award in 2008. For his "pioneering research into a new class of molecules" for "lowering cholesterol," Endo was inducted into the National Inventors Hall of Fame in Alexandria, Virginia in 2012. Michael C. 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."
^Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J, Qizilbash N, Peto R, Collins R (December 2007). "Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths". Lancet370 (9602): 1829–39. doi:10.1016/S0140-6736(07)61778-4. PMID18061058.
^Taylor F, Ward K, Moore TH, Burke M, Davey Smith G, Casas JP, Ebrahim S (2011). "Statins for the primary prevention of cardiovascular disease". Cochrane Database Syst Rev (1): CD004816. doi:10.1002/14651858.CD004816.pub4. PMID21249663.
^ abNaci H, Brugts J, Ades T (2013). "Comparative tolerability and harms of individual statins: a study-level network meta-analysis of 246 955 participants from 135 randomized, controlled trials". Circ Cardiovasc Qual Outcomes6 (4): 390–9. doi:10.1161/CIRCOUTCOMES.111.000071. PMID23838105.
^National Cholesterol Education Program (2001). 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. Bethesda, MD: National Institutes of Health. National Heart, Lung, and Blood Institute. p. 40. NIH Publication No. 01-3670.
^Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, Ward K, Ebrahim S (2013). "Statins for the primary prevention of cardiovascular disease". Cochrane Database Syst Rev1: CD004816. doi:10.1002/14651858.CD004816.pub5. PMID23440795.
^Petretta M, Costanzo P, Perrone-Filardi P, Chiariello M (2010). "Impact of gender in primary prevention of coronary heart disease with statin therapy: a meta-analysis". Int. J. Cardiol.138 (1): 25–31. doi:10.1016/j.ijcard.2008.08.001. PMID18793814.
^Ray KK, Seshasai SR, Erqou S, Sever P, Jukema JW, Ford I, Sattar N (2010). "Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants". Arch. Intern. Med.170 (12): 1024–31. doi:10.1001/archinternmed.2010.182. PMID20585067.
^Stone, NJ; Robinson, J; Lichtenstein, AH; Merz, CN; Blum, CB; Eckel, RH; Goldberg, AC; Gordon, D; Levy, D; Lloyd-Jones, DM; McBride, P; Schwartz, JS; Shero, ST; Smith SC, Jr; Watson, K; Wilson, PW (Nov 12, 2013). "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.". Circulation129 (25 Suppl 2): S1–S45. doi:10.1161/01.cir.0000437738.63853.7a. PMID24222016.
^Grupo de Trabajo de la Sociedad Europea de Cardiología (ESC) y de la Sociedad Europea de Aterosclerosis, (EAS); Reiner, Z; Catapano, AL; De Backer, G; Graham, I; Taskinen, MR; Wiklund, O; Agewall, S; Alegría, E; John Chapman, M; Durrington, P; Erdine, S; Halcox, J; Hobbs, R; Kjekshus, J; Perrone Filardi, P; Riccardi, G; Storey, RF; Wood, D (Dec 2011). "ESC/EAS Guidelines for the management of dyslipidaemias.". Revista espanola de cardiologia (English ed.)64 (12): 1168. doi:10.1016/j.rec.2011.09.015. PMID24776417.
^Zhou Z, Rahme E, Pilote L (2006). "Are statins created equal? Evidence from randomized trials of pravastatin, simvastatin, and atorvastatin for cardiovascular disease prevention". Am. Heart J.151 (2): 273–81. doi:10.1016/j.ahj.2005.04.003. PMID16442888.
^ abVuorio, A; Kuoppala, J; Kovanen, PT; Humphries, SE; Strandberg, T; Tonstad, S; Gylling, H (Jul 7, 2010). "Statins for children with familial hypercholesterolemia.". The Cochrane database of systematic reviews (7): CD006401. doi:10.1002/14651858.CD006401.pub2. PMID20614444.
^Lamaida, N; Capuano, E; Pinto, L; Capuano, E; Capuano, R; Capuano, V (Sep 2013). "The safety of statins in children.". Acta paediatrica (Oslo, Norway : 1992)102 (9): 857–62. doi:10.1111/apa.12280. PMID23631461.
^Mancini GB, Baker S, Bergeron J, et al. (2011). "Diagnosis, prevention, and management of statin adverse effects and intolerance: proceedings of a Canadian Working Group Consensus Conference". Can J Cardiol27 (5): 635–62. doi:10.1016/j.cjca.2011.05.007. PMID21963058.
^Finegold JA, Manisty CH, Goldacre B, Barron AJ, Francis DP (April 2014). "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". Eur J Prev Cardiol21 (4): 464–74. doi:10.1177/2047487314525531. PMID24623264.Cite uses deprecated parameters (help)
^Mancini GB, Tashakkor AY, Baker S, et al. (December 2013). "Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Working Group Consensus update". Can J Cardiol29 (12): 1553–68. doi:10.1016/j.cjca.2013.09.023. PMID24267801.Cite uses deprecated parameters (help)
^Mancini GB, Baker S, Bergeron J, et al. (2011). "Diagnosis, prevention, and management of statin adverse effects and intolerance: proceedings of a Canadian Working Group Consensus Conference". Can J Cardiol27 (5): 635–62. doi:10.1016/j.cjca.2011.05.007. PMID21963058.
^Ghirlanda G, Oradei A, Manto A, Lippa S, Uccioli L, Caputo S, Greco AV, Littarru GP (1993). "Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study". J Clin Pharmacol33 (3): 226–9. doi:10.1002/j.1552-4604.1993.tb03948.x. PMID8463436.
^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 (2010). "Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials". Lancet375 (9716): 735–42. doi:10.1016/S0140-6736(09)61965-6. PMID20167359.
^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 (2011). "Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis". JAMA305 (24): 2556–64. doi:10.1001/jama.2011.860. PMID21693744.
^Jukema JW, Cannon CP, de Craen AJ, Westendorp RG, Trompet S (Sep 4, 2012). "The controversies of statin therapy: weighing the evidence.". Journal of the American College of Cardiology60 (10): 875–81. doi:10.1016/j.jacc.2012.07.007. PMID22902202.
^Alsheikh-Ali AA, Maddukuri PV, Han H, Karas RH (2007). "Effect of the Magnitude of Lipid Lowering on Risk of Elevated Liver Enzymes, Rhabdomyolysis, and Cancer: Insights from Large Randomized Statin Trials". Journal of the American College of Cardiology50 (5): 409–418. doi:10.1016/j.jacc.2007.02.073. PMID17662392.
^Alsheikh-Ali AA, Karas RH (March 2009). "The relationship of statins to rhabdomyolysis, malignancy, and hepatic toxicity: evidence from clinical trials.". Current atherosclerosis reports11 (2): 100–4. doi:10.1007/s11883-009-0016-8. PMID19228482.
^Singh S, Singh AG, Singh PP, Murad MH, Iyer PG (June 2013). "Statins are associated with reduced risk of esophageal cancer, particularly in patients with Barrett's esophagus: a systematic review and meta-analysis.". Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association11 (6): 620–9. doi:10.1016/j.cgh.2012.12.036. PMID23357487.
^Liu Y, Tang W, Wang J, Xie L, Li T, He Y, Deng Y, Peng Q, Li S, Qin X (Nov 22, 2013). "Association between statin use and colorectal cancer risk: a meta-analysis of 42 studies.". Cancer causes & control : CCC25 (2): 237–49. doi:10.1007/s10552-013-0326-6. PMID24265089.
^Wu XD, Zeng K, Xue FQ, Chen JH, Chen YQ (October 2013). "Statins are associated with reduced risk of gastric cancer: a meta-analysis.". European journal of clinical pharmacology69 (10): 1855–60. doi:10.1007/s00228-013-1547-z. PMID23748751.
^Singh PP, Singh S (July 2013). "Statins are associated with reduced risk of gastric cancer: a systematic review and meta-analysis.". Annals of oncology : official journal of the European Society for Medical Oncology / ESMO24 (7): 1721–30. doi:10.1093/annonc/mdt150. PMID23599253.
^Pradelli D, Soranna D, Scotti L, Zambon A, Catapano A, Mancia G, La Vecchia C, Corrao G (May 2013). "Statins and primary liver cancer: a meta-analysis of observational studies.". European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP)22 (3): 229–34. doi:10.1097/cej.0b013e328358761a. PMID23010949.
^Zhang Y, Zang T (2013). "Association between statin usage and prostate cancer prevention: a refined meta-analysis based on literature from the years 2005–2010.". Urologia internationalis90 (3): 259–62. doi:10.1159/000341977. PMID23052323.
^Zhang XL, Liu M, Qian J, Zheng JH, Zhang XP, Guo CC, Geng J, Peng B, Che JP, Wu Y (Jul 23, 2013). "Statin use and risk of kidney cancer: a meta-analysis of observational studies and randomized trials.". British Journal of Clinical Pharmacology. doi:10.1111/bcp.12210. PMID23879311.
^Undela K, Srikanth V, Bansal D (August 2012). "Statin use and risk of breast cancer: a meta-analysis of observational studies.". Breast cancer research and treatment135 (1): 261–9. doi:10.1007/s10549-012-2154-x. PMID22806241.
^Cui X, Xie Y, Chen M, Li J, Liao X, Shen J, Shi M, Li W, Zheng H, Jiang B (July 2012). "Statin use and risk of pancreatic cancer: a meta-analysis.". Cancer causes & control : CCC23 (7): 1099–111. doi:10.1007/s10552-012-9979-9. PMID22562222.
^Zhang XL, Geng J, Zhang XP, Peng B, Che JP, Yan Y, Wang GC, Xia SQ, Wu Y, Zheng JH (April 2013). "Statin use and risk of bladder cancer: a meta-analysis.". Cancer causes & control : CCC24 (4): 769–76. doi:10.1007/s10552-013-0159-3. PMID23361339.
^Saito Y, Yoshida S, Nakaya N, Hata Y, Goto Y (Jul–Aug 1991). "Comparison between morning and evening doses of simvastatin in hyperlipidemic subjects. A double-blind comparative study". Arterioscler Thromb11 (4): 816–26. doi:10.1161/01.ATV.11.4.816. PMID2065035.
^Cilla DD, Gibson DM, Whitfield LR, Sedman AJ (July 1996). "Pharmacodynamic effects and pharmacokinetics of atorvastatin after administration to normocholesterolemic subjects in the morning and evening". Journal of Clinical Pharmacology36 (7): 604–9. doi:10.1002/j.1552-4604.1996.tb04224.x. PMID8844442.
^Lahera V, Goicoechea M, de Vinuesa SG, Miana M, de las Heras N, Cachofeiro V, Luño J (2007). "Endothelial dysfunction, oxidative stress and inflammation in atherosclerosis: beneficial effects of statins". Curr Med Chem14 (2): 243–8. doi:10.2174/092986707779313381. PMID17266583.
^de Lorgeril M, Salen P, Abramson J, Dodin S, Hamazaki T, Kostucki W, Okuyama H, Pavy B, Rabaeus M (Jun 28, 2010). "Cholesterol lowering, cardiovascular diseases, and the rosuvastatin-JUPITER controversy: a critical reappraisal.". Archives of Internal Medicine170 (12): 1032–6. doi:10.1001/archinternmed.2010.184. PMID20585068.
^Safety of Statins: Focus on Clinical Pharmacokinetics and Drug Interactions" Circulation 2004:109:III-50-IIIi-57
^"Metabolism of cerivastatin by human liver microsomes in vitro. Characterization of primary metabolic pathways and of cytochrome P450 isozymes involved". Drug Metab Dispos25 (3): 321–31. Mar 1997.
^Comparison of Cytochrome P-450-Dependent Metabolism and Drug Interactions of the 3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitors Lovastatin and Pravastatin in the Liver. DMD February 1, 1999 vol. 27 no. 2 173–179
^Shepherd J, Hunninghake DB, Barter P, McKenney JM, Hutchinson HG (2003). "Guidelines for lowering lipids to reduce coronary artery disease risk: a comparison of rosuvastatin with atorvastatin, pravastatin, and simvastatin for achieving lipid-lowering goals". Am. J. Cardiol.91 (5A): 11C–17C; discussion 17C–19C. doi:10.1016/S0002-9149(03)00004-3. PMID12646338.
^"Crystal and Molecular Structure of Compactin, a New Antifungal Metabolite from Penicillium brevicompactum." Alian G. Brown, Terry C. Smale, Trevor J. King, Rainer Hasenkamp and Ronald H. Thompson. J. Chem. Soc., Perkin Trans. 1, 1976, 1165–1170. doi:10.1039/P19760001165
^Steinberg, Daniel. The Cholesterol Wars: The Skeptics vs. The Preponderance of Evidence. Academic Press, 2007, pp. 6–9.
^"Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)". Lancet344 (8934): 1383–9. November 1994. doi:10.1016/S0140-6736(94)90566-5. PMID7968073.
^Golomb BA, Dimsdale JE, White HL, Ritchie JB, Criqui MH (April 2008). "Reduction in blood pressure with statins: results from the UCSD Statin Study, a randomized trial". Arch. Intern. Med.168 (7): 721–7. doi:10.1001/archinte.168.7.721. PMID18413554.