Statin



  The statins (or HMG-CoA reductase inhibitors) form a class of low-density lipoprotein (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

History

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).[1]

The first agent isolated was 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.

Indications and uses

Statins, the most potent cholesterol-lowering agents available, lower LDL cholesterol (so-called "bad cholesterol") by 30–50%.[2] However, they have less effect than the 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 intravascular ultrasonography.[4]

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.

Research continues into other areas where statins also appear to have a favorable effect: inflammation, dementia,[5] cancer,[6] nuclear cataracts,[7] and pulmonary hypertension.

Members

The statins are divided into two groups: synthetic.

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

Statin Brand name Derivation
Atorvastatin Lipitor, Torvast Synthetic
adverse effects) Synthetic
Fluvastatin Lescol, Lescol XL 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)
Vytorin Combination therapy
Niacin extended-release Advicor Combination therapy
Caduet Combination therapy - Cholesterol+Blood Pressure

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.[8] The relative potency of pitavastatin has not yet been fully established.

Safety

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) levels are decreased in statin use;[9] Q10 supplements are sometimes used to treat statin-associated myopathy, though evidence of their effectiveness is currently lacking.[10]

One 2004 study found that of 10,000 patients treated for one year, 0.44 will develop rhabdomyolysis. 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[12]). 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 number needed to treat would approximate 5000, making statins unlikely tools for primary prevention.[13]

Drug interactions

Combining any statin with a 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—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.

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.[15]

Mode of action

Cholesterol lowering

Main articles: Lipoprotein

  Most circulating cholesterol is manufactured internally, in amounts of about 1000 mg/day, via steroid biosynthesis through the 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, an amount 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 very low density lipoprotein (VLDL) carry cholesterol toward 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 LDL receptors, leading to increased clearance of low-density lipoprotein from the bloodstream.[16]

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.[4]

Non-cholesterol related actions

Statins exhibit action beyond lipid-lowering activity in the prevention of atherosclerosis. Researchers hypothesize that statins prevent cardiovascular disease via four proposed mechanisms (all subjects of a large body of biomedical research):[17]

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

Controversy

Some scientists take a skeptical view of the need for many people to require statin treatment. The International Network of Cholesterol Skeptics is a group that has questioned the "lipid hypothesis" that supports cholesterol lowering as a preventive measure for heart disease, and has argued that statins - especially at higher doses - may not be as beneficial or safe as suggested.[18] Similarly, some authors argue that recommendations for the expanded use of statins to stave off cardiovascular disease are not supported by evidence.[19]

References

  1. ^ Endo A. The discovery and development of HMG-CoA reductase inhibitors. J Lipid Res 1992;33:1569-82. PMID 1464741.
  2. ^ 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. PMID 9514454.
  3. ^ Wilson P, D'Agostino R, Levy D, Belanger A, Silbershatz H, Kannel W (1998). "Prediction of coronary heart disease using risk factor categories". Circulation 97 (18): 1837-47. PMID 9603539.
  4. ^ a b 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.
  5. ^ 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. doi:10.1186/1741-7015-5-20. PMID 17640385. Retrieved on 2007-09-24.
  6. ^ 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. PMID 17494779.
  7. ^ Klein, Barbara E. K., MD, MPH; Klein, Ronald, MD, MPH; Lee, Kristine E., MS; Grady, Lisa M., BS (June 21 2006). "Statin Use and Incident Nuclear Cataract". Journal of the American Medical Association 295 (23): 2752-8. PMID 16788130. Retrieved on 2007-01-24.
  8. ^ 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. PMID 12646338.
  9. ^ 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. PMID 8463436.
  10. ^ 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. doi:10.1016/j.jacc.2007.02.049. PMID 17560286.
  11. ^ 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.
  12. ^ Dale KM, Coleman CI, Henyan NN, Kluger J, White CM. Statins and cancer risk: a meta-analysis. JAMA 2006;295:74-80. PMID 16391219.
  13. ^ 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.
  14. ^ Kane GC, Lipsky JJ. Drug-grapefruit juice interactions. Mayo Clin Proc 2000;75:933-42. PMID 10994829.
  15. ^ 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.
  16. ^ 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.
  17. ^ Furberg, Curt D. (1999). "Natural Statins and Stroke Risk". Circulation 99: 185-188. American Heart Association. Retrieved on 2007-03-04.
  18. ^ Ravnskov U, Rosch P, Sutter M, Houston M (2006). "Should we lower cholesterol as much as possible?". BMJ 332 (7553): 1330-2. PMID 16740566.
  19. ^ Abramson J, Wright J (2007). "Are lipid-lowering guidelines evidence-based?". Lancet 369 (9557): 168-9. PMID 17240267.
 
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