Statin

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Statins are drugs that are used to lower cholesterol or lipid levels. Of all the drugs that affect lipid metabolism , they have the highest potency. The non-proprietary names ( INN ) of their representatives end in -statin .

From a biochemical point of view, a statin is a drug from the substance class of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase ( HMG-CoA reductase ) inhibitors (also known as HMG-CoA reductase inhibitors ). Statins are also known under the term CSE inhibitors ( cholesterol synthesis enzyme inhibitors ).

In endocrinology, the inhibiting hormones are also referred to as statins; but this is only a matter of identical names.

The first statin was mevastatin (laboratory name ML-236B, also called compactin), which occurs in the fungus Penicillium citrinum and whose lipid-lowering effect was first described in 1976 by the Japanese researcher Akira Endo .

Mode of action

Statins as lipid lowering agents

The effect of statins as lipid-lowering agents is based on their competitive inhibition of HMG-CoA reductase . Since HMG-CoA is a substance that the body needs for the biosynthesis of cholesterol , less cholesterol is produced by the body itself under the action of statins than without it. Since there is a relative lack of cholesterol in the cells, they produce more LDL receptors, which take up the low-density lipoprotein from the blood through endocytosis . LDL is primarily responsible for most of the damage to the body caused by high cholesterol levels. This removes LDL from the bloodstream, reducing the level of LDL in the blood and thus also the effects of LDL such as arteriosclerosis .

The administration of statins causes a reduction in heart attacks and deaths. The independent research association Cochrane comes to the conclusion: "Of 1000 people who would be treated with statins over a period of five years, 18 could avoid a major HKE event." There are no significant differences in the effectiveness of pravastatin, simvastatin or atorvastatin in their standard dosages in reducing heart attacks or deaths.

Risk reduction through the administration of statins

There are publications in which referring to scientific studies

  • a significant reduction in the frequency of death from heart attack by 42%,
  • a statistically highly significant reduction in overall mortality of 30% ,
  • a highly significant risk reduction for vascular events of 22%

by lowering LDL cholesterol levels with statins. This information is based on the relative risk reduction determined in the studies rather than on an absolute risk reduction or on the number of necessary treatments (NNT), which expresses how many patients must be treated in order for one to benefit from the therapy. The CTT meta-analysis from November 2010 with 129,526 test persons over an observation period of 4.8 years shows a reduction for "first major vascular events" of 2.77% and for "all-cause mortality" of 1.91% in the case of an LDL Reduction of 1.0 mmol / l. This means an absolute reduction in cardiovascular events of 2-3% when taking statins for a period of about 5 years. These explanations show that a distinction must be made between relative and absolute risk reduction in order to assess the benefit of taking statins. The independent research association Cochrane comes to the conclusion: "Of 1000 people who would be treated with statins over a period of five years, 18 could avoid a major HKE event."

Statins as plaque stabilizers

The positive effects that statins have on the survival of patients after cardiovascular events (such as heart attack) cannot be explained solely by the expansion of constrictions in the coronary arteries. It is now assumed that statins have an indirect anti-inflammatory effect on unstable atherosclerotic deposits (plaques). Oxidized LDL, which is stored in unstable plaques, appears to attract inflammatory cells such as monocytes and lymphocytes. As part of the inflammation of the plaque that has developed in this way, matrix-degrading enzymes (matrix metalloproteinases) are formed. The matrix metalloproteinases in particular digest the structural protein collagen, which imparts mechanical strength to the plaques. The statins appear to reduce the storage of oxidized LDL. As a result, they prevent or reduce inflammatory cell migration and the formation of matrix metalloproteases . The increased presence of collagen in this way increases plaque stability in the long term, although the thickness of the deposits (and thus the narrowing of the vessel) does not decrease, or only slightly decreases.

Statins as immunomodulators

Statins are used in controlled studies for immune modulation .

Transplant surgery

A study published in 2003 compared 39 lung transplant patients receiving statin treatment for hyperlipidaemia with 161 transplant recipients without statin treatment. Significant results: In the statin group there were fewer acute rejection reactions , no obliterative bronchiolitis compared to 37% in the comparison group, a lower number of inflammatory cells in the blood test, better spirometry results and a significantly higher six-year survival.

multiple sclerosis

In 2002, a study was published that showed that mice suffering from chronic experimental autoimmune encephalitis (EAE), a disease similar to MS, can reduce the production of specific T cells and other markers of inflammation. This has now been demonstrated for atorvastatin , lovastatin and simvastatin .

In a study published in 2003, 30 patients with relapsing MS were treated with 80 mg simvastatin daily. This showed a 43 percent lower increase in demyelinating foci, which was detected using magnetic resonance imaging .

A double-blind, randomized study published in 2013 on 140 patients with secondary progressive MS showed that taking 80 mg of simvastatin resulted in 40% less loss of brain volume and slower progression.

Statins for cancer

A meta-analysis of previous studies published in 2006 (N = 27) on the effect on cancer with data from approx. 90,000 patients found statin use to be ineffective - "neutral" - i.e. H. neither useful nor harmful. No cancer types or circumstances could be identified in which the incidence , course or prognosis of the disease would be significantly influenced by statins .

An epidemiological study published in 2012 using data from the Danish Cancer Registry showed that patients over 40 years of age were significantly less likely to die of cancer if a statin was taken during life (and overall mortality was also reduced by the same amount). The investigation could not show any reasons for this correlation . Not recorded were e.g. B. smoking status, participation in a mammography screening, intake of ASA or metformin (both drugs show evidence of a cancer preventive effect).

Statins for heart attack

Statins offer decades of protection for blood vessels. A long-term study found that men treated with statins 20 years ago had a significantly lower death rate of 13 percent.

Statins in old age with severe illness

In elderly patients with severe illness, the benefits of statins are not positive when taking side effects and quality of life into account.

indication

Statins are used for isolated hypercholesterolemia , such as polygenic hypercholesterolemia or familial hypercholesterolemia (as the first choice ), but also for combined hyperlipidemia , for primary and secondary prophylaxis of arteriosclerosis and associated cardiovascular events.

Side effects

The main side effect of statins is muscle discomfort. If 10,000 people are treated with an effective statin dose for 5 years, 50–100 patients with muscle pain or weakness without increased creatine kinase (CK) can be expected, in 5 with myopathy with an increase in CK and in 1 with rhabdomyolysis . Randomized placebo-controlled studies have shown that side effects associated with statin therapy are not always caused by statins. A pronounced nocebo effect can be assumed. The muscle-damaging mechanism is the subject of research, but there is a dose-response effect.

The most serious side effects of statins include what are known as toxic myopathies . These are structural and functional changes in the skeletal muscles. The most severe form of toxic myopathy is rhabdomyolysis , which leads to the destruction of the striated muscles . Up to 2003, about 3350 cases of rhabdomyolysis caused by lipid-lowering drugs had been described in the literature. The strength of the different statins is different. More than 100 fatal cases of rhabdomyolysis in connection with the use of cerivastatin (trade name: Lipobay), especially in combination with gemfibrozil , resulted in the drug being withdrawn from the market in 2001. Fluvastatin has the lowest frequency of myopathy, although it has one of the weakest lipid-lowering effects even at the highest dose. Based on long-term observations, in October 2012 the FDA issued  changes to the information for use for almost all statins - including those in combination with niacin - that refer to immune-mediated necrotizing myopathy ( IMNM ).

In a study published in 2013 it was found that statins lead to a worsened increase in cardiovascular fitness during exercise. This is not only due to the myalgias mentioned above , but also to the drop in citrate synthase , an important enzyme for aerobic energy production from mitochondria.

The Australian Medicines Agency switched all statins from pregnancy category C to the more stringent category D in 2005. This translates into published observations that statins have shown teratogenic effects not only in animal experiments but also in humans , since cholesterol is an essential building block for fetal development. Pregnant women should therefore no longer take statins. In Germany, statins have been classified as contraindicated for pregnant women since their market launch .

Until 2005, isolated cases of memory loss associated with statin use were reported. In addition, there are individual indications of a decline in memory and alertness as well as increased aggressiveness and increased irritability in connection with the use of statins. Individual case reports suggest a link between the use of statins and the occurrence of nightmares.

Other side effects such as a connection between the use of statins and the development of dementia or a connection with cataracts could be refuted.

Kidney damage from statins is possible. According to a study published in 2013, there is an increase in hospitalization due to kidney problems, especially in the first two years of therapy.

Statins slightly increase the risk of diabetes mellitus . A meta-analysis shows almost 100,000 patients with a slightly increased risk of diabetes from statins of 9 percent or one additional case of diabetes per 255 patients in four years. On the other hand, it was calculated from the studies that the same therapy could prevent 5.4 fatal and non-fatal heart attacks per 255 patients in four years and per 1 mmol / l or 40 mg / dl LDL lowering. In addition, there is a decrease in strokes and revascularizing interventions, which is why the risk-benefit ratio for statins is good.

Gynecomastia is a rare side effect of statins . In addition, the production of brown adipose tissue can be reduced and its activity restricted.

Representatives, studies

See also: Studies on Cholesterol

Atorvastatin

  • Trade names: Sortis (Germany), Lipitor (USA) + Generika
  • First manufacturer: Pfizer

Atorvastatin is mainly metabolized via CYP 3A4 , which is why inhibitors of this CYP enzyme, e.g. B. amiodarone or grapefruit juice , can lead to increased blood levels and more severe side effects.

Cerivastatin

  • Trade names: Lipobay, Baycol, Zenas
  • First manufacturer: Bayer AG

Lipobay was withdrawn from the market in 2001 due to its side effects. Up to September 2001 a total of 19 suspected fatal side effects ( rhabdomyolysis ) in connection with statin treatment (all statins) were reported. Of the ten cases involving cerivastatin, the drug is likely to have actually led to the patient's death in four cases, and thus statistically significantly more often than other statins. Based on current knowledge, the withdrawal from the market was therefore justified on the basis of existing alternative preparations. The majority of cases were attributed to drug interaction with the fibrate gemfibrozil at the highest dose of cerivastatin.

Fluvastatin

  • Trade names: Cranoc, Lescol, Locol, Fractal + Generika
  • First manufacturer: Fujisawa Pharmaceutical
  • Studies: ALERT

Fluvastatin is one of the weaker statins, but also the best tolerated statin and is sold by the companies Astellas Pharma GmbH , Novartis and as a generic. In contrast to almost all other statins, fluvastatin is not broken down by CYP3A4 but by CYP2C9 .

Lovastatin

  • Trade names: Mevinacor + Generika
  • First manufacturer: MSD Sharp & Dohme
  • Studies: Lovastatin Study Group III

Lovastatin was one of the statins with which Merck began its first (animal) studies in 1980. However, since Sankyo discontinued a study with the almost structurally identical compactin due to an increased occurrence of side effects, Merck also terminated the studies for the time being. Lovastatin occurs naturally in red fermented rice .

Pitavastatin

  • Trade names: Livalo, Pitava
  • First manufacturer: Sankyo Pharmaceuticals Ltd .; Tokyo, Japan / Zydus Cadila - India

Pravastatin

Rosuvastatin

  • Trade name: Crestor
  • First manufacturer: AstraZeneca / Shionogi
  • Studies: AURORA, COMET, JUPITER

Rosuvastatin is the youngest member of the statins group. The profile of the effect and the side effects basically corresponds to that of the other statins.

Simvastatin

  • Trade names: Cholib, Gerosim, Zocor, Zocord + Generika
  • First manufacturer: MSD Sharp & Dohme , Hexal AG
  • Studies: 4S, Heart Protection Study

Simvastatin is mainly metabolized via CYP 3A4, but like lovastatin and fluvastatin also via CYP 2D6. Therefore, poor metabolisers with CYP 2D6 have higher blood levels and increased side effects.

market

Lipitor (USA) and Sortis (EU), each with the active ingredient atorvastatin, were the world's most successful statin. In 2004 it had sales of $ 10.7 billion. In 2007 (according to Forbes.com ) worldwide sales of 12.8 billion US dollars were achieved. Since the introduction of atorvastatin generics (in Germany 2012), sales have declined significantly.

literature

Individual evidence

  1. ↑ oA: Les statines en question . In: Le Journal du Médecin (Belgique) 2013, edition 2304 of March 8, 2013, p. 14.
  2. ↑ Aktories: Pharmacology and Toxicology . 9th edition.
  3. ↑ a b Statins for the primary prevention of cardiovascular diseases. Retrieved February 9, 2020 .
  4. ^ Z Zhou, E Rahme, L. Pilote: Are statins created equal? Evidence from randomized trials of pravastatin, simvastatin, and atorvastatin for cardiovascular disease prevention . In: Am Heart J , 2006 Feb, 151 (2), pp. 273-281, PMID 16442888 .
  5. ↑ Helmut Gohlke: The Cholesterol Lie . (PDF; 75 kB).
  6. ↑ know what counts . ( Memento from June 26, 2013 in the Internet Archive ) lipid-liga.de
  7. ↑ New studies, new discussions, but no new rules: Cholesterol-lowering drugs protect risk patients . DGN, press release of February 3, 2011.
  8. ↑ Cholesterol Treatment Trialists' (CTT) Collaboration: Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomized trials . (PDF; 382 kB) In: The Lancet . 2010 November 13; 376 (9753), pp. 1670-1681.
  9. ↑ Non-invasive characterization of arteriosclerosis using magnetic resonance1 . ( Memento of October 17, 2007 in the Internet Archive ) (PDF)
  10. ^ Statin Use Is Associated with Improved Function and Survival of Lung Allografts . In: American Journal of Respiratory and Critical Care Medicine , Vol. 167, No. 9, 2003, pp. 1271-1278, doi: 10.1164 / rccm.200205-410OC .
  11. ↑ Sawsan Youssef, Olaf Stueve, Juan C. Patarroyo, Pedro J. Ruiz, Jennifer L. Radosevich, Eun Mi Hur, Manuel Bravo, Dennis J. Mitchell, Raymond A. Sobel, Lawrence Steinman, Scott S. Zamvil: The HMG- CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. In: Nature . 420, 2002, pp. 78-84, doi: 10.1038 / nature01158 .
  12. ^ Neuhaus et al .: Statins as immunomodulators: Comparison with interferon- {beta} 1b in MS . ( Memento of the original from May 22, 2009 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. In: Neurology , 59 (7), p. 990. @1@ 2Template: Webachiv / IABot / www.neurology.org
  13. ↑ MS Research - Promising US pilot study: Cholesterol-lowering drug "Simvastatin" as an MS inhibitor? Multiple Sclerosis News.
  14. ↑ The MS-Stat Trial: High Dose Simvastatin Slows Brain Atrophy and Delays Disability in Secondary Progressive Multiple Sclerosis: A Phase II Placebo-Controlled Trial (PL02.001) - Chataway et al. 80 (1001): PL02.001 - Neurology . The MS-Stat Trial: High Dose Simvastatin Slows Brain Atrophy and Delays Disability in Secondary Progressive Multiple Sclerosis, neurology.org, accessed January 26, 2014.
  15. ^ Statins and Cancer Risk. A meta-analysis. In: JAMA , 2006, 295, pp. 74-80, PMID 16391219 .
  16. ^ Sune F. Nielsen, Børge G. Nordestgaard, Stig E. Bojesen: Statin Use and Reduced Cancer-Related Mortality . In: New England Journal of Medicine , 2012, Volume 367, Issue 19, November 8, 2012, doi: 10.1056 / NEJMoa1201735
  17. ↑ Statins could lower cancer mortality . Deutsches Ärzteblatt online, November 8, 2012; Retrieved January 26, 2014.
  18. ↑ aerztezeitung.de
  19. ^ JS Kutner: Safety and benefit of discontinuing statin therapy . In: JAMA Intern Med. , 2015 May 1; 175 (5), pp. 691-700.
  20. ↑ Therapy with statins: acceptable risk and clear benefit with adequate indication . In: WD Ludwig, J Schuler (ed.): The drug letter . tape 51 . Westkreuz Verlag, Berlin, p. 19 .
  21. ↑ HMGCoA reductase inhibitor (statin) drugs- Risk of immune-mediated necrotizing myopathy (IMNM) label changes . MedWatch, at IMNM , October 2012.
  22. ↑ CR Mikus, LJ Boyle, SJ Borengasser, DJ Oberlin, SP Naples, J. Fletcher, GM Meers, M. Ruebel, MH Laughlin, KC Dellsperger, PJ Fadel, JP Thyfault: Simvastatin impairs exercise training adaptations. In: Journal of the American College of Cardiology . [electronic publication before printing] April 2013, doi: 10.1016 / j.jacc.2013.02.074 . PMID 23583255 .
  23. ↑ Acute memory loss with atorvastatin and simvastatin . UAW-News - International, Drugs Commission of the German Medical Association, announcements February 2005; Retrieved February 26, 2014.
  24. ^ PJ Gregoor: Atorvastatin may cause nightmares . In: BMJ . 332, No. 7547, April 2006, p. 950. doi : 10.1136 / bmj.332.7547.950 . PMID 16627511 . PMC 1444869 (free full text).
  25. ↑ Less cataracts, less dementia: statins are not only good for the heart .
  26. ^ Statins prevent cataracts . ( Memento of the original from October 15, 2013 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. @1@ 2Template: Webachiv / IABot / www.escardio.org
  27. ↑ High dose statins prevent dementia . ( Memento of the original from November 9, 2013 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. @1@ 2Template: Webachiv / IABot / www.escardio.org
  28. ↑ CR Dormuth, BR Hemmelgarn, JM Paterson, MT James, GF Teare, CB Raymond, JP Lafrance, A. Levy, AX Garg, P. Ernst: Use of high potency statins and rates of admission for acute kidney injury: multicenter, retrospective observational analysis of administrative databases. In: BMJ (Clinical research ed.). Volume 346, 2013, p. F880, PMID 23511950 .
  29. ^ N. Sattar et al .: Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials . Lancet Online, February 17, 2010, quoted from MMW-Fortschr. Med. , No. 10/2010, 152nd volume, p. 25.
  30. ↑ G. Roberto, C. Biagi, N. Montanaro, A. Koci, U. Moretti, D. Motola: Statin-associated gynecomastia: evidence coming from the Italian spontaneous ADR reporting database and literature. In: European Journal of Clinical Pharmacology . Volume 68, Number 6, June 2012, pp. 1007-1011, doi : 10.1007 / s00228-012-1218-5 , PMID 22286160 .
  31. ↑ inhibition of mevalonates Pathway Prevents adipocyte Browning in Mice and Men by Affecting protein prenylation . In: Cell Metabolism . December 20, 2018, doi : 10.1016 / j.cmet.2018.11.017 .