Statin

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The statins (or HMG-CoA reductase inhibitors) form a class of hypolipidemic agents, used as pharmaceuticals to lower cholesterol levels in people with or at risk for cardiovascular disease. They cause cholesterol lowering by inhibiting the enzyme HMG-CoA reductase, an enzyme involved in the rate of cholesterol synthesis. Inhibition of this enzyme in the liver stimulates the LDL-receptors, which results in an increased clearance of LDL from the bloodstream and a decrease in blood cholesterol levels. The first results can be seen after one week of use and the effect is maximal after four to six weeks.

Contents 1 Members 2 Mode of action 2.1 Cholesterol lowering 2.2 Non-cholesterol related actions 3 Indications and uses 4 Pharmacogenomics 5 Safety 5.1 Adverse effects 5.2 Drug interactions 6 History 7 References

[edit] Members

The statins are divided into two groups: Fermentation-derived and Synthetic. Fermentation-derived statins appear more effective in reducing LDL, but no clear explanation has accounted for this phenomenon^[1].

The statins include, in alphabetical order (brand names vary in different countries):

Statin	Brand name	Derivation
Atorvastatin	Lipitor, Torvast	Synthetic
Cerivastatin	Lipobay, Baycol. (Withdrawn from the market in 2001 due to risk of serious adverse effects)	Synthetic
Fluvastatin	Lescol	Synthetic
Lovastatin	Mevacor, Altocor	Fermentation-derived
Mevastatin	-	Naturally-occurring compound. Found in red yeast rice.
Pitavastatin	Livalo, Pitava	Synthetic
Pravastatin	Pravachol, Selektine, Lipostat	Fermentation-derived
Rosuvastatin	Crestor	Synthetic
Simvastatin	Zocor, Lipex	Fermentation-derived. (Simvastatin is a synthetic derivate of a fermentation product)

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.^{[citation needed]} The relative potency of pitavastatin has not yet been fully established.

[edit] Mode of action

[edit] Cholesterol lowering

Main articles: Cholesterol and Lipoprotein

Most circulating cholesterol is manufactured internally, typically about 1000 mg/24 hours, out of the carbohydrate metabolism, by the HMG-CoA reductase pathway. Cholesterol, both from dietary intake and secreted into the duodenum as bile from the liver, is typically absorbed at a rate of 50% by the small intestines. The typical diet in the United States and many other Western countries, is estimated as adding about 200-300 mg/day to intestinal intake; much smaller than that secreted into the intestine in the bile. Thus internal production is an important factor.

Cholesterol is not water-soluble, and is therefore carried in the blood in the form of lipoproteins, the type being determined by the apoprotein, a protein coating that acts as an emulsifier. The relative balance between these lipoproteins is determined by various factors, including genetics, diet, insulin resistance. Low density lipoprotein (LDL) and very low density lipoprotein (VLDL) carry cholesterol towards tissues, and elevated levels of these lipoproteins are associated with atheroma formation (fat-containing deposits in the arterial wall) and cardiovascular disease. High density lipoprotein, in contrast, carries cholesterol back to the liver and is associated with protection against cardiovascular disease.

Statins act by competitively inhibiting HMG-CoA reductase, the first committed enzyme of the HMG-CoA reductase pathway. By reducing intracellular cholesterol levels, they cause liver cells to upregulate expression of the LDL receptor, leading to increased clearance of low-density lipoprotein from the bloodstream.^[2]

Direct evidence of the action of statin-based cholesterol lowering on atherosclerosis was presented in the ASTEROID trial, which demonstrated regression of atheroma employing intravascular ultrasound.^[3]

[edit] Non-cholesterol related actions

Statins exhibit action beyond lipid-lowering activity in the prevention of atherosclerosis. Researchers believe that statins prevent cardiovascular disease via four proposed mechanisms (all subjects of a large body of biomedical research):^[1]

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

[edit] Indications and uses

Statins, the most potent cholesterol-lowering agents, lower LDL-cholesterol (so-called "bad cholesterol") by 30–50%.^{[citation needed]} However, 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. In practice, however, a cholesterol reduction of more than 10% is unusual, and many patients do not achieve their targets through dietary approaches.^{[citation needed]}

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 e.g. the Framingham risk score^[4]). 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, and achieving lower than usual target calculated LDL values, showed disease regression within the heart arteries using IVUS.^[5]

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, indeed dominant and increasing role in both the primary and secondary prevention coronary heart disease, myocardial infarction, stroke and peripheral artery disease.

Research continues into other areas where statins also appear to have a favorable effect: inflammation, dementia, neoplastic conditions and pulmonary hypertension.

[edit] Pharmacogenomics

A 2004 study showed that patients with one of two common single nucleotide polymorphisms (small genetic variations) in the HMG-CoA reductase gene were less responsive to statins^[6].

[edit] Safety

[edit] Adverse effects

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.

A clearer major safety concern, myositis, myopathy, rarely with rhabdomyolysis (the pathological breakdown of skeletal muscle) may lead to acute renal failure when muscle breakdown products damage the kidney. Co-Enzyme Q-10 (ubiquinone) has shown promise in reducing statin-associated myalgias (statins block production of ubiquinone in addition to cholesterol).^{[citation needed]} One 2004 study found that of 10,000 patients treated for one year, 0.44 will develop this side-effect. Cerivastatin, which was withdrawn by its manufacturer for this reason in 2001, had a much higher incidence (more than 10x)^[7]. All commonly used statins show somewhat similar results, however the newer statins, characterized by longer pharmacological half-lifes 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.

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^[8]). 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^[9].

[edit] Drug interactions

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^[7]. 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 and some other medications^[10] (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.

[edit] History

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)^[11].

The first agent isolated was mevastatin (ML-236B), a molecule produced by 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 mold Aspergillus terreus. Dr Endo was awarded the 2006 Japan Prize for his work on the development of statins.

[edit] References

1. ^ ^{a b} Furberg CD. Natural statins and stroke risk. Circulation 1999;99:185-188. PMID 9892578.
2. ^ Ma PT, Gil G, Sudhof TC, Bilheimer DW, Goldstein JL, Brown MS. 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 1986;83:8370-4. PMID 3464957.
3. ^ Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, Davignon J, Erbel R, Fruchart JC, Tardif JC, Schoenhagen P, Crowe T, Cain V, Wolski K, Goormastic M, Tuzcu EM; ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295:1556-65. PMID 16533939.
4. ^ Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation 1998;97:1837-47. PMID 9603539.
5. ^ 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. PMID 16533939.
6. ^ Chasman DI, Posada D, Subrahmanyan L, Cook NR, Stanton VP Jr, Ridker PM. Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA 2004;291:2821-7. PMID 15199031.
7. ^ ^{a b} Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L, Gurwitz JH, Chan KA, Goodman MJ, Platt R. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004;292:2585-90. PMID 15572716.
8. ^ Dale KM, Coleman CI, Henyan NN, Kluger J, White CM. Statins and cancer risk: a meta-analysis. JAMA 2006;295:74-80. PMID 16391219.
9. ^ Poynter JN, Gruber SB, Higgins PD, Almog R, Bonner JD, Rennert HS, Low M, Greenson JK, Rennert G. Statins and the risk of colorectal cancer. N Engl J Med 2005;352:2184-92. PMID 15917383.
10. ^ Kane GC, Lipsky JJ. Drug-grapefruit juice interactions. Mayo Clin Proc 2000;75:933-42. PMID 10994829.
11. ^ Endo A. The discovery and development of HMG-CoA reductase inhibitors. J Lipid Res 1992;33:1569-82. PMID 1464741.

Statins (C10AA) edit
Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin