Statin

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Statin
Drug class
Lovastatin
Lovastatin, a compound isolated from Aspergillus terreus, was the first statin to be marketed.
Use High cholesterol
Biological target HMG-CoA reductase
ATC code C10AA
External links
MeSH D019161
AHFS/Drugs.com Drug Classes

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. Increased cholesterol levels have been associated with cardiovascular disease (CVD).[1] 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). However, the evidence is weaker that statins are effective for those with elevated cholesterol levels but without CVD (primary prevention).[2][3][4] Side effects of statins include muscle pain, increased risk of diabetes and abnormalities in liver enzyme tests.[5] Additionally they have rare but severe adverse effects, particularly muscle damage.[6] Moreover, some doctors believe that statins are over-prescribed.

As of 2010, a number of statins are on the market: atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), pitavastatin (Livalo), pravastatin (Pravachol), rosuvastatin (Crestor) and simvastatin (Zocor).[7] Several combination preparations of a statin and another agent, such as ezetimibe/simvastatin, are also available. The best-selling statin is atorvastatin which by 2003 became the best-selling pharmaceutical in history.[8] The manufacturer Pfizer reporting sales of US$12.4 billion in 2008.[9]

Medical uses[edit]

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.[10][11]

Primary prevention[edit]

Debate exists over whether statins are effective in those with high cholesterol, but no history of heart disease.[12] The best meta-analysis (with individual patient data) did not find a mortality benefit in those at high risk but without prior cardiovascular disease.[12] Other reviews concluded there is a mortality and morbidity benefit,[13][14] but there were concerns regarding the quality of the evidence.[4] With respect to quality of life, evidence of improvement is limited when statins are used for primary prevention.[4] No studies as of 2010 show improved clinical outcomes in children with high cholesterol though statins decrease cholesterol levels.[15]

Secondary prevention[edit]

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.[2] 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.[16] They have less effect than the fibrates or niacin in reducing triglycerides and raising HDL-cholesterol ("good cholesterol").

Comparative effectiveness[edit]

While no direct comparison exists, all statins appear effective regardless of potency or degree of cholesterol reduction.[14] There do appear to be some differences between them, with simvastatin and pravastatin appearing superior in terms of side-effects.[5]

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.[17]

Controversy[edit]

Some[quantify] scientists believe the statins are overused. Their use has expanded into areas where they provide lesser benefit, and lesser evidence of benefit. The lower the risk of cardiovascular events, the lower the ratio is of benefits to costs. The US market for statins nearly tripled when the National Cholesterol Education Program revised its guidelines to recommend statins as primary prevention. Although the panel cited randomized trials to support statin therapy for primary prevention of occlusive cardiovascular disease, a report in Lancet notes, "not one of the studies provides such evidence." [18]

A group of scientists, The International Network of Cholesterol Skeptics, question the lipid hypothesis and argue that elevated cholesterol has not been adequately shown to cause heart disease. These organizations maintain that statins are not as beneficial or safe as suggested.[19] The beneficial effects of statins are suggested to be due to their working as vitamin D analogues.[20]

Adverse effects[edit]

Choosing a statin for people with special considerations[21]
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.[22]
HIV-positive people taking protease inhibitors Atorvastatin, Pravastatin or Fluvastatin Significant negative interactions are more likely with other choices[23]
persons taking gemfibrozil, a non-statin cholesterol-lowering drug Atorvastatin Combining gemfibrozil and a statin increases risk of Rhabdomyolysis and subsequently renal failure[24][25]
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.[26]

The most common adverse side effects are raised liver enzymes and muscle problems. In randomized clinical trials, reported adverse effects are low; but they are "higher in studies of real world use", and more varied.[27] In randomized trials, 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.[28] However, reliance on clinical trials can be misleading indications of real-world adverse effects – for example, the statin cerivastatin was withdrawn from the market in 2001 due to cases of rhabdomyolysis (muscle breakdown), although rhabdomyolysis was not found in a meta-analysis of published cerivastatin clinical trials.[27] A 2014 systematic review on the side effects of statins found a 0.5% increase in diabetes.[29] Other possible adverse effects include cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction.[27]

Some people on statin therapy report myalgias,[30] muscle cramps,[30] or, less frequently, gastrointestinal or other symptoms. Liver enzyme derangements, typically in about 0.5%,[citation needed] 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 these are causally related to statins in some individuals.[31] A Danish case-control study published in 2002 suggested a relationship between long-term statin use and increased risk of nerve damage or polyneuropathy,[32] but suggested this side effect is "rare, but it does occur";[33] 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.[34]

Muscles[edit]

Problems with muscles occur in 10-15% of people who take statins.[6] Rare reactions include myositis and myopathy, with the potential for rhabdomyolysis (a significant breakdown of skeletal muscle) leading to possibly acute renal failure. Coenzyme Q10 (ubiquinone) levels are decreased in statin use;[35] CoQ10 supplements are sometimes used to treat statin-associated myopathy, though there was not enough evidence of their effectiveness despite their ability to raise the circulating levels of CoQ10 in blood plasma as of 2007.[36] 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.[37]

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.[38] 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.[citation needed] 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;[39] 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.[citation needed] Lovastatin induces the expression of gene atrogin-1, which is believed to be responsible in promoting muscle fiber damage.[39]

Diabetes[edit]

Statins may increase the risk of diabetes by 9%,[40] with higher doses appearing to have a larger effect.[41]

Cancer[edit]

Statins do not appear to be associated with cancer.[42][43] Although there have been concerns that they might increase risk,[44] several meta-analyses have found no relationship.[45][46]

They may reduce the risk of esophageal cancer,[47] colorectal cancer,[48] gastric cancer,[49][50] hepatocellular carcinoma,[51] and possibly prostate cancer.[52][53] They appear to have no effect on the risk of lung cancer,[54] kidney cancer,[55] breast cancer,[56] pancreatic cancer,[57] or bladder cancer.[58]

Drug interactions[edit]

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.[38] 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.[59] 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[60] (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.[61]

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 raise 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.[62]

Mechanism of action[edit]

Atorvastatin bound to HMG-CoA reductase: PDB entry 1hwk[63]
The HMG-CoA reductase pathway, which is blocked by statins via inhibiting the rate limiting enzyme HMG-CoA reductase.

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. A variety of statins are produced by Penecillium and Aspergillus fungi as secondary metabolites. These natural statins probably function to inhibit HMG-CoA reductase enzymes in bacteria and fungi that compete with the producer.[64]

Inhibiting cholesterol synthesis[edit]

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,[65] 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,[66][67] but have shown no difference in the long-acting atorvastatin.[68]

Increasing LDL uptake[edit]

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.[69] 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[edit]

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."[70] 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,[71][72] and may also account for certain of the benefits seen in cancer reduction with statins.[73]

Other effects[edit]

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.[74] Researchers hypothesize that statins prevent cardiovascular disease via four proposed mechanisms (all subjects of a large body of biomedical research):[75]

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

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.[76] 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.[77]

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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Statin Pathway edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430". 

Pharmacogenomics[edit]

A 2004 study showed patients with one of two common single-nucleotide polymorphisms (SNPs) (small genetic variations) in the HMG-CoA reductase gene were less responsive to statins.[78] A 2008 study showed carriers of the KIF6 genetic mutation were more responsive to statin treatment.[79]

Myopathy Adverse Drug Event[edit]

Likewise, a 2008 study demonstrated a link between an increased risk of myopathy at higher doses of statins (40–80 mg) and a SNP in SLCO1B1, a gene encoding for the organic anion transporter peptide OATP1B1.[37] Genotyping or genome sequencing can be used to investigate preemptively to avoid myopathy in patients with increased risk.[80] This risk is determined by the single nucleotide polymorphism rs4149056, also known as 37041T>C or V174A. The rs4149056(C) SNP defines the SLCO1B1*5 allele of the SLCO1B1 gene.

History[edit]

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.[8] 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).[64] 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.[81] 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.[8]

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.[82]

To market statins effectively, Merck had to convince the public about the dangers of high cholesterol, and doctors that statins were safe and would extend lives. As a result of public campaigns, people 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%.[8][83] In 1995, Zocor and Mevacor both made Merck over US$1 billion.[8] Endo was awarded the 2006 Japan Prize, and the Lasker-DeBakey Clinical Medical Research Award in 2008.

Available forms[edit]

The statins are divided into two groups: fermentation-derived and synthetic. They include, along with brand names, which may vary between countries:

Statin Image Brand name Derivation Metabolism[84]
Atorvastatin
Lipitor.png
Lipitor, Torvast Synthetic CYP3A4
Cerivastatin
Cerivastatin.png
Lipobay, Baycol. (Withdrawn from the market in August, 2001 due to risk of serious Rhabdomyolysis) Synthetic various CYP3A isoforms [85]
Fluvastatin
Fluvastatine.png
Lescol, Lescol XL Synthetic CYP2C9
Lovastatin
Lovastatin.png
Mevacor, Altocor, Altoprev Fermentation-derived. Naturally occurring compound. Found in oyster mushrooms and red yeast rice. CYP3A4
Mevastatin
Mevastatin.png
Compactin Naturally occurring compound. Found in red yeast rice. CYP3A4
Pitavastatin
Pitavastatin structure.png
Livalo, Pitava Synthetic
Pravastatin
Pravastatin.svg
Pravachol, Selektine, Lipostat Fermentation-derived. (A fermentation product of bacterium Nocardia autotrophica). Non CYP[86]
Rosuvastatin
Rosuvastatin-Formulae V 1.png
Crestor Synthetic CYP2C9 and CYP2C19
Simvastatin
Simvastatin.svg
Zocor, Lipex Fermentation-derived. (Simvastatin is a synthetic derivate of a fermentation product ofAspergillus terreus.) CYP3A4
Simvastatin+Ezetimibe Vytorin Combination therapy
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, (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.[87] The relative potency of pitavastatin has not yet been fully established.

The oyster mushroom, a culinary mushroom, naturally contains lovastatin.

Some types of statins are naturally occurring, and can be found in such foods as oyster mushrooms and red yeast rice. Randomized controlled trials found them to be effective, but the quality of the trials was low.[88] Most of the block-buster branded statins will be generic by 2012, including atorvastatin, the largest-selling branded drug.

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
56–60% 40 mg
* 80-mg dose no longer recommended due to increased risk of rhabdomyolysis
Starting dose
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 mg/dL (4.87 mmol/L) 40 mg if >45%
Optimal timing Anytime Evening With evening meals Anytime Anytime Evening

Research[edit]

Research continues into other areas where specific statins also appear to have a favorable effect, including dementia,[89] lung cancer,[90] nuclear cataracts,[91] hypertension,[92] and prostate cancer.[93]

References[edit]

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  21. ^ table adapted from the following source, but check individual references for technical explanations
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