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The statins (or HMG-CoA reductase inhibitors) are a class of drugs that lower cholesterol levels in people.
They lower cholesterol by inhibiting the enzyme HMG-CoA reductase, which is the rate-limiting enzyme of the mevalonate pathway of cholesterol synthesis. Inhibition of this enzyme in the liver results in decreased cholesterol synthesis as well as increased synthesis of LDL receptors, resulting in an increased clearance of low-density lipoprotein (LDL) from the bloodstream. The first results can be seen after one week of use and the effect is maximal after four to six weeks.
- See also: Statin development
Akira Endo and Masao Kuroda of Tokyo, Japan commenced research into inhibitors of HMG-CoA reductase in 1971 (Endo 1992). This 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 wall (ergosterol) or cytoskeleton (isoprenoids).
The first agent isolated was mevastatin (ML-236B), a molecule produced by the fungus Penicillium citrinum. The pharmaceutical company Merck & Co. showed an interest in the Japanese research in 1976, and isolated lovastatin (mevinolin, MK803), the first commercially marketed statin, from the fungus Aspergillus terreus. Dr. Endo was awarded the 2006 Japan Prize for his work on the development of statins, and the Clinical Medical Research Award from the Lasker Foundation in 2008.
Mechanism of action
- Main article: Cholesterol#Homeostasis
Statins act by competitively inhibiting HMG-CoA reductase, the first committed enzyme of the HMG-CoA reductase pathway. Because statins are similar to HMG-CoA on a molecular level they take the place of HMG-CoA in the enzyme and reduce the rate by which it is able to produce mevalonate, the next molecule in the cascade that eventually produces cholesterol, as well as a number of other compounds. This ultimately reduces cholesterol via several mechanisms.
Inhibiting cholesterol synthesis
By inhibiting HMG-CoA reductase, statins block the pathway for synthesizing cholesterol in the liver. This is significant because most circulating cholesterol comes from internal manufacture rather than the diet. When the liver can no longer produce cholesterol, levels of cholesterol in the blood will fall. Cholesterol synthesis appears to occur mostly at night, 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
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 and are digested.
Statins exhibit action beyond lipid-lowering activity in the prevention of atherosclerosis. The ASTEROID trial showed direct ultrasound evidence of atheroma regression during statin therapy. Researchers hypothesize that statins prevent cardiovascular disease via four proposed mechanisms (all subjects of a large body of biomedical research):
- Improve endothelial function
- Modulate inflammatory responses
- Maintain plaque stability
- Prevent thrombus formation
Statins may even benefit those without high cholesterol. In 2008 the JUPITER study showed fewer stroke, heart attacks, and surgeries even for patients who had no history of high cholesterol or heart disease, but only elevated C-reactive protein levels. There were also 20% fewer deaths (mainly from reduction in cancer deaths) though deaths from cardiovascular causes were not reduced.
Statins have been linked to a marked reduction in prostate cancer, benign prostate enlargement, incontinence and impotence in older men.
Indications and uses
Statins, the most potent cholesterol-lowering agents available, lower LDL cholesterol (so-called "bad cholesterol") by 1.8 mmol/l. This translates in a 60% decrease in the number of cardiac events (heart attack, sudden cardiac death), and a 17% reduced risk of stroke. They have less effect than the fibrates or niacin in reducing triglycerides and raising HDL-cholesterol ("good cholesterol"). Professional guidelines generally require that the patient has tried a cholesterol-lowering diet before statin use is considered; statins or other pharmacologic agents may then be recommended for patients who do not meet their lipid-lowering goals through diet and lifestyle approaches.
The indications for the prescription of statins have broadened over the years. Initial studies, such as the Scandinavian Simvastatin Survival Study (4S), supported the use of statins in secondary prevention for cardiovascular disease, or as primary prevention only when the risk for cardiovascular disease was significantly raised (as indicated by the Framingham risk score). Indications were broadened considerably by studies such as the Heart Protection Study (HPS), which showed preventative effects of statin use in specific risk groups, such as diabetics. The ASTEROID trial, published in 2006, using only a statin at high dose, achieved lower than usual target calculated LDL values and showed disease regression within the coronary arteries using intravascular ultrasonography.
Based on clinical trials, the National Cholesterol Education Program guidelines, and the increasing focus on aggressively lowering LDL-cholesterol, the statins continue to play an important role in both the primary and secondary prevention of coronary heart disease, myocardial infarction, stroke and peripheral artery disease.
Fermentation-derived and synthetic
The statins include, in alphabetical order (brand names vary in different countries):
|Cerivastatin||Lipobay, Baycol. (Withdrawn from the market in August, 2001 due to risk of serious Rhabdomyolysis)||Synthetic|
|Fluvastatin||Lescol, Lescol XL||Synthetic|
|Lovastatin||Mevacor, Altocor, Altoprev||Fermentation-derived. Naturally-occurring compound. Found in oyster mushrooms and red yeast rice.|
|Mevastatin||-||Naturally-occurring compound. Found in red yeast rice.|
|Pravastatin||Pravachol, Selektine, Lipostat||Fermentation-derived|
|Simvastatin||Zocor, Lipex||Fermentation-derived. (Simvastatin is a synthetic derivate of a fermentation product)|
|Lovastatin+Niacin extended-release||Advicor||Combination therapy|
|Atorvastatin+Amlodipine Besylate||Caduet||Combination therapy - Cholesterol+Blood Pressure|
|Simvastatin+Niacin extended-release||Simcor||Combination therapy|
LDL-lowering potency varies between agents. Cerivastatin is the most potent, 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 found them to be effective, but the quality of the trials was low..
No large scale comparison exists that examines the relative effectiveness of the various statins against one another for preventing hard cardiovascular outcomes, such as death or myocardial infarction.
An independent analysis has been done to compare atorvastatin, pravastatin and simvastatin, based on their effectiveness against placebos. It found that, at commonly prescribed doses, there are no statistically significant differences amongst statins in reducing cardiovascular morbidity and mortality. The CURVES study, which compared the efficacy of different doses of atorvastatin, simvastatin, pravastatin, lovastatin, and fluvastatin for reducing LDL and total cholesterol in patients with hypercholesterolemia, found that atorvastatin was more effective without increasing adverse events.
Statins differ in their ability to reduce cholesterol levels. Doses should be individualized according to patient characteristics such as goal of therapy and response. After initiation and/or dose changes, lipid levels should be analyzed within 1–3 months and dosage adjusted accordingly, then every 6–12 months afterwards.    
|Statin Equivalent Dosages|
|% LDL Reduction (approx.)||Atorvastatin||Fluvastatin||Lovastatin||Pravastatin||Rosuvastatin||Simvastatin|
|10-20%||--||20 mg||10 mg||10 mg||--||5 mg|
|20-30%||--||40 mg||20 mg||20 mg||--||10 mg|
|30-40%||10 mg||80 mg||40 mg||40 mg||5 mg||20 mg|
|40-45%||20 mg||--||80 mg||80 mg||5–10 mg||40 mg|
|46-50%||40 mg||--||--||--||10–20 mg||80 mg|
|50-55%||80 mg||--||--||--||20 mg||--|
|Starting dose||10–20 mg||20 mg||10–20 mg||40 mg||10 mg; 5 mg if hypothyroid, >65 yo, Asian;||20 mg|
|If higher LDL reduction goal||40 mg if >45%||40 mg if >25%||20 mg if >20%||--||20 mg if LDL >190||40 mg if >45%|
|Optimal timing||Anytime||Evening||With evening meals||Anytime||Anytime||Evening|
Statins vary in cost from $4 to $150 a month in the USA. Some are available as low as $4.00 for a month's supply through Wal-Mart pharmacies.Consumer Reports recommends generic lovastatin, pravastatin, and simvastatin as cost-efficient "Best Buy" alternatives to more expensive branded drugs, for those in whom it is suitable.
Statins are perceived as well-tolerated, and raised liver enzymes and muscle problems are the only common adverse effects. Reported adverse effects are low in clinical trials but "higher in studies of real world use", and more varied. Statins increased the risk of an adverse effect by 39% compared to placebo (odds ratios 1.4); two-thirds of these were myalgia or raised liver enzymes with serious adverse effects similar to placebo.
While some patients on statin therapy report myalgias, muscle cramps, or far less-frequent gastrointestinal or other symptoms, similar symptoms are also reported with placebo use in all the large statin safety/efficacy trials and usually resolve, either on their own or on temporarily lowering/stopping the dose. Liver enzyme derangements may also occur, typically in about 0.5%, are also seen at similar rates with placebo use and repeated enzyme testing, and generally return to normal either without discontinuance over time or after briefly discontinuing the drug. Multiple other side-effects occur rarely; typically also at similar rates with only placebo in the large statin safety/efficacy trials. Two randomized clinical trials found cognitive issues while two did not; recurrence upon reintroduction suggests that these are causally related to statins in some individuals. One Danish study in 2002 suggested a relation between long term statin use and increased risk of nerve damage or polyneuropathy but suggested this side effect is "rare, but it does occur"; other researchers have pointed to studies of the effectiveness of statins in trials involving 50,000 people which have not shown nerve damage as a significant side effect.
More serious but rare reactions include myositis and myopathy, with the potential for rhabdomyolysis (the pathological breakdown of skeletal muscle) leading to acute renal failure. Coenzyme Q10 (ubiquinone) levels are decreased in statin use; Q10 supplements are sometimes used to treat statin-associated myopathy, though evidence of their effectiveness is currently lacking. A common variation in the SLCO1B1 gene, which participates in the absorption of statins, has been shown 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 tenfold greater if cerivastatin was used, or if the standard statins (atorvastatin, fluvastatin, lovastatin, pravastatin, 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, however 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. The risk of myopathy is lowest with pravastatin and fluvastatin probably because they are more hydrophillic 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.
Despite initial concerns that statins might increase the risk of cancer, various studies concluded later that statins have no influence on cancer risk (including the heart protection study and a 2006 meta-analysis). Indeed, a 2005 trial showed that patients taking statins for over 5 years reduced their risk of colorectal cancer by 50%; this effect was not exhibited by fibrates. The trialists warn that the number needed to treat would approximate 5000, making statins unlikely tools for primary prevention. However, in a recent meta-analysis of 23 statin treatment arms with 309,506 person-years of follow-up, there was an inverse relationship between achieved LDL-cholesterol levels and rates of newly diagnosed cancer that the authors claim requires further investigation.
Combining any statin with a fibrate, 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 statins—furanocoumarins in grapefruit juice 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 (it had been thought that flavonoids were responsible). This increases the levels of the statin, increasing the risk of dose-related adverse effects (including myopathy/rhabdomyolysis). Consequently, consumption of grapefruit juice is not recommended in patients undergoing therapy with most statins. An alternative, somewhat risky, approach is that some users take grapefruit juice to enhance the effect of lower (hence cheaper) doses of statins. This is not recommended as a result of the increased risk and potential for statin toxicity.
A 2008 study showed that carriers of the KIF6 genetic mutation were more responsive to statin treatment.
Some scientists take a skeptical view of the need for many people to require statin treatment. Given the wide indications for which statins are prescribed, and the declining benefit in groups at lower baseline risk of cardiovascular events, the evidence base for expanded statin use has been questioned by some researchers. A much smaller minority, exemplified by The International Network of Cholesterol Skeptics, question the "lipid hypothesis" itself and argue that elevated cholesterol has not been adequately linked to heart disease. These groups claim that statins are not as beneficial or safe as suggested.
- ↑ Julio Alarcon, Sergio Aguila, Patricia Arancibia-Avila, Oscar Fuentes, Enrique Zamorano-Ponce, and Margarita Hernandez (2003). Production and Purification of Statins from Pleurotus ostreatus (Basidiomycetes) Strains. Z. Naturforsch. 58c: 62–64.
- ↑ Endo A (1 November 1992). The discovery and development of HMG-CoA reductase inhibitors. J. Lipid Res. 33 (11): 1569–82.
- ↑ Miettinen TA (March 1982). Diurnal variation of cholesterol precursors squalene and methyl sterols in human plasma lipoproteins. Journal of Lipid Research 23 (3): 466–73.
- ↑ 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 Thromb 11.
- ↑ Wallace A; Chinn D; Rubin G (4 October 2003). Taking simvastatin in the morning compared with in the evening: randomised controlled trial. British Medical Journal 327.
- ↑ Cilla DD Jr; Gibson DM; Whitfield LR; Sedman AJ (July 1996). Pharmacodynamic effects and pharmacokinetics of atorvastatin after administration to normocholesterolemic subjects in the morning and evening 36.
- ↑ Ma PT, Gil G, Südhof TC, Bilheimer DW, Goldstein JL, Brown MS (1986). Mevinolin, an inhibitor of cholesterol synthesis, induces mRNA for low density lipoprotein receptor in livers of hamsters and rabbits. Proc. Natl. Acad. Sci. U.S.A. 83 (21): 8370–4. Full text at PMC: 386930
- ↑ 8.0 8.1 Nissen S, Nicholls S, Sipahi I, Libby P, Raichlen J, Ballantyne C, Davignon J, Erbel R, Fruchart J, Tardif J, Schoenhagen P, Crowe T, Cain V, Wolski K, Goormastic M, Tuzcu E (2006). Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 295 (13): 1556–65.
- ↑ Furberg CD (19 January 1999). Natural Statins and Stroke Risk. Circulation 99 (2): 185–188.
- ↑ Ridker PM, Danielson E, Fonseca FAH, et al. (2008). Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. NEJM 359 (21): 2195–207.
- ↑ Cholesterol Drugs May Protect Prostate, Sex Potency, Study Says, Bloomberg, 2009-04-26
- ↑ Law MR, Wald NJ, Rudnicka AR (June 2003). Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 326 (7404): 1423.
- ↑ Wilson P, D'Agostino R, Levy D, Belanger A, Silbershatz H, Kannel W (19 May 1998). Prediction of coronary heart disease using risk factor categories. Circulation 97 (18): 1837–47.
- ↑ Kodach LL, Bleuming SA, Peppelenbosch MP, Hommes DW, van den Brink GR, Hardwick JC. The effect of statins in colorectal cancer is mediated through the bone morphogenetic protein pathway. Gastroenterology 2007 133:1272-81. | PMID: 17919499 |
- ↑ Wolozin, B, Wang SW, Li NC, Lee A, Lee TA, Kazis LE (July 19, 2007). Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease. BMC Medicine 5: 20. Full text at PMC: 1955446
- ↑ Khurana, V, Bejjanki HR, Caldito G, Owens MW (May 2007). Statins reduce the risk of lung cancer in humans: a large case-control study of US veterans. Chest 131 (5): 1282–1288.
- ↑ Klein BE, Klein R, Lee KE, Grady LM (June 2006). Statin use and incident nuclear cataract. JAMA 295 (23): 2752–8.
- ↑ 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.
- ↑ 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.
- ↑ Gunde-Cimerman N, Cimerman A. (Mar 1995). Pleurotus fruiting bodies contain the inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase-lovastatin.. Exp Mycol. 19 (1): 1–6.
- ↑ Liu J, Zhang J, Shi Y, Grimsgaard S, Alraek T, Fønnebø V (2006). Chinese red yeast rice (Monascus purpureus) for primary hyperlipidemia: a meta-analysis of randomized controlled trials. Chin Med 1: 4.
- ↑ 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.
- ↑ Jones P, Kafonek S, Laurora I, Hunninghake D (1998). Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 81 (5): 582–7.
- ↑ Ryan Oftebro, PharmD. HMG-CoA Reductase Inhibitors (“Statins”): Clinical Pearls for Washington Rx Therapeutic Interchange Program (TIP). Accessed 2009-11-22.
- ↑ Common Medication Conversions (Equivalents): Statins (HMG-CoA Reductase Inhibitors) GlobalRPh.com. Accessed 2009-11-22.
- ↑ Treating Elevated Cholesterol and Heart Disease: The Statins. Consumer Reports Health Best Buy Drugs. February 2007
- ↑ Dosage information including FDA approved labels (package inserts) from DailyMed United States National Library of Medicine.
- ↑ Consumer Reports Health.org, Statins: Summary of Recommendations. February 2007
- ↑ 29.0 29.1 Golomb BA, Evans MA (2008). Statin adverse effects : a review of the literature and evidence for a mitochondrial mechanism. Am J Cardiovasc Drugs 8 (6): 373–418.
- ↑ Silva MA, Swanson AC, Gandhi PJ, Tataronis GR (January 2006). Statin-related adverse events: a meta-analysis. Clin Ther 28 (1): 26–35.
- ↑ 31.0 31.1 includeonly>Anne Harding. "Docs often write off patient side effect concerns", Reuters, Aug 28, 2007. Retrieved on 2009-10-06.
- ↑ Holman JR. (2007). Some Docs in Denial About Statin Side Effects. Doc News.
- ↑ includeonly>D. Gaist, MD PhD. "Statins and risk of polyneuropathy -- A case-control study", American Academy of Neurology, 2002;58, pp. 1333–1337. Retrieved on 2009-10-06.
- ↑ includeonly>Julie Appleby and Steve Sternberg. "Cholesterol drug cited in nerve study", USA TODAY, 08/20/2002. Retrieved on 2009-10-06.
- ↑ includeonly>Sandra G. Boodman, The Washington Post. "Study links statins to nerve damage", Pittsburgh Post-Gazette, September 10, 2002. Retrieved on 2009-10-06.
- ↑ includeonly>Julie Appleby and Steve Sternberg. "Statin side effect rare, but be aware", USA TODAY, 2008. Retrieved on 2009-10-06.
- ↑ Ghirlanda G, Oradei A, Manto A, Lippa S, Uccioli L, Caputo S, Greco A, Littarru G (1993). Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study. J Clin Pharmacol 33 (3): 226–9.
- ↑ Marcoff L, Thompson PD (2007). The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J. Am. Coll. Cardiol. 49 (23): 2231–7.
- ↑ (July 2008)SLCO1B1 Variants and Statin-Induced Myopathy -- A Genomewide Study. N. Engl. J. Med. Online (8): 789.
- ↑ 40.0 40.1 Graham DJ, Staffa JA, Shatin D, et al. (2004). Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 292 (21): 2585–90.
- ↑ Hanai J, Cao P, Tanksale P, et al. (2007). The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity. J. Clin. Invest. 117 (12): 3940–51.
- ↑ Dale KM, Coleman CI, Henyan NN, Kluger J, White CM (2006). Statins and cancer risk: a meta-analysis. JAMA 295 (1): 74–80.
- ↑ Poynter JN, Gruber SB, Higgins PD, et al. (2005). Statins and the risk of colorectal cancer. N. Engl. J. Med. 352 (21): 2184–92.
- ↑ Alsheikh-Ali AA (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 Cardiology 50 (5): 409–418.
- ↑ Kane GC, Lipsky JJ (2000). Drug-grapefruit juice interactions. Mayo Clin. Proc. 75 (9): 933–42.
- ↑ Chasman DI, Posada D, Subrahmanyan L, Cook NR, Stanton VP, Ridker PM (2004). Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA 291 (23): 2821–7.
- ↑ Iakoubova O, Marc S. Sabatine, Charles M. Rowland, et al. Polymorphism in KIF6 Gene and Benefit From Statins After Acute Coronary Syndromes. Journal of the American College of Cardiology. 2008; 51(4): 449-455.
- ↑ Abramson J, Wright J (2007). Are lipid-lowering guidelines evidence-based?. Lancet 369 (9557): 168–9.
- ↑ Ravnskov U, Rosch P, Sutter M, Houston M (2006). Should we lower cholesterol as much as possible?. BMJ 332 (7553): 1330–2.
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