Zusammenfassung
HMG-CoA-Reduktase-Hemmer (Statine) sind potente Cholesterinsenker und werden seit
vielen Jahren zur medikamentösen Behandlung der Hypercholesterinämie eingesetzt. Darüber
hinaus sind die Statine zur Sekundärprophylaxe der koronaren Herzkrankheit (KHK) selbst
bei durchschnittlichen Cholesterinspiegeln indiziert, wie in großen klinischen Studien
(4S, CARE, LIPID, u. a.) nachgewiesen wurde. Obwohl Hypercholesterinämie kein eindeutiger
Risikofaktor für den ischämischen Schlaganfall ist, zeigte sich in diesen Studien
auch eine signifikante Reduktion der Schlaganfallinzidenz bei Patienten mit einer
manifesten KHK. Ob Statine auch generell zur Sekundärprophylaxe des Schlaganfalls
indiziert sind, ist jedoch noch unklar und wird in laufenden Studien (PROSPER, SPARCL)
untersucht. Sowohl klinische als auch experimentelle Daten sprechen für cholesterinunabhängige,
protektive Wirkungen der Statine auf vaskulärer, thrombozytärer, inflammatorischer
und möglicherweise auch neuronaler Ebene (sog. pleiotrope Effekte). Weiterhin gibt
es erste klinische Hinweise sowie viel versprechende experimentelle Daten für eine
mögliche Wirksamkeit von Statinen bei Demenzen. Bezüglich einer möglichen Wirksamkeit
von Statinen bei weiteren neurologischen Erkrankungen, wie z. B. Hirntumoren oder
neuroimmunologischen Erkrankungen, liegen momentan lediglich erste experimentelle
Befunde vor. Eine evidenzbasierte Indikation für Statine in der Neurologie ergibt
sich derzeit lediglich zur Schlaganfallprophylaxe bei Patienten mit manifester KHK.
Abstract
HMG-CoA reductase inhibitors (statins) are potent cholesterol-lowering drugs and are
established for the treatment of hypercholesterolemia. Furthermore, large clinical
trials (4S, CARE, LIPID) demonstrated that statins are indicated for secondary prophylaxis
of coronary heart disease (CHD) even in patients with average cholesterol levels.
Although hypercholesterolemia is not an established risk factor for ischemic stroke,
these studies demonstrated that statins also reduce stroke incidence in patients with
CHD. The question whether or not statins are generally indicated for secondary prevention
of stroke is subject of two ongoing trials (i.e. PROSPER, SPARCL). Clinical as well
as experimental evidence supports the notion that statins exert cholesterol-independent
(so-called „pleiotropic”) protective effects. These include anti-inflammatory and
anti-thrombotic effects, improvement of endothelial function and even direct neuroprotective
effects. Furthermore, experimental and preliminary clinical studies suggest a potential
role of statins for the treatment of dementia. Regarding the use of statins in clinical
neurology, current evidence only supports the use for stroke prophylaxis in patients
with a history of CHD.
Literatur
- 1
Levine G NJ, Keany J F, Vita J A.
Cholesterol reduction in cardiovascular disease.
N Engl J Med.
1995;
332
512-521
- 2
Goldstein J L, Browns M S.
Regulation of the mevalonate pathway.
Nature.
1990;
343
425-430
- 3
Furberg C D.
Natural statins and stroke risk.
Circulation.
1999;
99
185-188
- 4
Moghadasian M H.
Clinical pharmacology of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.
Life Sci.
1999;
65 (13)
1329-1337
- 5
Hamelin B A, Turgeon J.
Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects
of HMG-CoA reductase inhibitors.
Trends Pharmacol Sci.
1998;
19
26-37
- 6
Davidson M H.
Safety profiles for the HMG-CoA reductase inhibitors: treatment and trust.
Drugs.
2001;
61 (2)
197-206
- 7
Omar M A, Wilson J P, Cox T S.
Rhabdomyolysis and HMG-CoA reductase inhibitors.
Ann Pharmacother.
2001;
35 (9)
1096-1107
- 8
de Pinieux G, Chariot P, Ammi-Said M. et al .
Lipid-lowering drugs and mitochondrial function: effects of HMG-CoA reductase inhibitors
on serum ubiquinone and lactate/pyruvate ratio.
B J Clin Pharmacol.
1996;
42
333-337
- 9
Laaksonen R, Jokelainen K, Laakso J. et al .
The effect of simvastatin treatment on natural antioxidants in low-density lipoproteins
and high-energy phosphates and ubiquinone in skeletal muscle.
Am J Cardiol.
1996;
77
851-854
- 10
Miller D B, Spence J D.
Clinical pharmacokinetics of fibric acid derivatives (fibrates).
Clin Pharmakokinet.
1998;
34
155-162
- 11
Shek A, Ferrill M J.
Statin-fibrate combination therapy.
Ann Pharmacother.
2001;
35
908-917
- 12
Zylka-Menhorn V.
Ringen um Arzneimittelsicherheit.
DÄ.
2001;
33
1796-1798
- 13
Dresser G K, Spence J D, Bailey D G.
Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome
P450 3A4 inhibition.
Clin Pharmacokinet.
2000;
38
41-57
- 14
Davidson M H.
Does differing metabolism by cytochrome p450 have clinical importance?.
Curr Atheroscler Rep.
2000;
2
14-19
- 15
Bearid S L.
HMG-CoA reductase inhibitors: assessing differences in drug interactions and safety
profiles.
J Am Pharm Assoc (Wash).
2000;
40
637-644
- 16
Lilja J J, Kivisto K T, Neuvonen P J.
Grapefruit juice increases serum concentration of atorvastatin and has no effect on
pravastatin.
Clin Pharmacol Ther.
1999;
66
118-127
- 17
Kantola T, Kivisto K T, Neuvonen P J.
Grapefruit juice greatly increases serum concentration of lovastatin and lovaststin
acid.
Clin Pharmacol Ther.
1998;
63
397-402
- 18
Jacobs D, Blackburn H, Higgins M. et al .
Report of the conference on low blood cholesterol: mortality associations.
Circulation.
1992;
86
1046-1060
- 19
Muldoon M F, Manuck S B, Matthews K A.
Lowering cholesterol concentrations and mortality: a quantitative review of primary
prevention trials.
BMJ.
1990;
301
309-314
- 20
Muldoon M F, Manuck S B, Mendelsohn A B. et al .
Colesterol reduction and non-illness mortality: meta-analysis of randomised clinical
trials.
BMJ.
2001;
322
11-15
- 21
Dawber T R, Kannel W B, McNamara P M, Cohen M E.
An epidemiological study of apoplexy (strokes), observation in 5209 adults of apoplexy.
Trans Am Neurol Assoc.
1965;
90
237-240
- 22
Prospective studies collaboration .
Cholesterol, diastolic blood pressure, and stroke: 13 000 strokes in 450 000 people
in 45 prospective cohorts.
Lancet.
1995;
346
1647-1653
- 23
Atkins D, Bruce M P, Koepsell T D. et al .
Cholesterol reduction and the risk for stroke in men. A meta-analysis of randomized,
controlled trials.
Ann Intern Med.
1993;
119
136-145
- 24
Hebert P R, Gaziano J M, Hennekens C H.
An overview of trials of cholesterol lowering and risk of stroke.
Arch Intern Med.
1995;
155
50-55
- 25
Amarenco P.
Hypercholesterolemia, lipid-lowering agents, and the risk for brain infarction.
Neurology.
2001;
57, Suppl 2
S35-S44
- 26
Eastern Stroke and Coronary Heart Disease Collaborative Research Group .
Blood pressure, cholesterol, and stroke in eastern Asia.
Lancet.
1998;
352
1801-1807
- 27
Hachinski V, Graffagnini C, Beaudry M. et al .
Lipids and stroke: a paradox resolved.
Arch Neurol.
1996;
53
303-308
- 28
Benfante R, Yano K, Hwang L J. et al .
Elevated serum cholesterol is a risk factor for both coronary heart disease and thromboembolic
stroke in Hawaiian Japanese men. Implications of shared risk.
Stroke.
1994;
25
814-820
- 29
Iso H, Jacobs D R, Wentworth D. et al .
For the MRFIT Research Group. Serum cholesterol levels and six-year mortality from
stroke in 350 977 men screened for the Multiple Risk Factor Intervention Trial.
N Engl J Med.
1989;
320
904-910
- 30
Yano K, Reed D M, MacLean C J.
Serum cholesterol and hemorrhagic stroke in the Honolulu Heart Program.
Stroke.
1989;
20
1460-1465
- 31
Iribarren C, Jacobs D R, Sadler M. et al .
Low total cholesterol and intracerebral hemorrhagic stroke: is the association confined
to elderly men? The Kaise Permanente Medical Care Program.
Stroke.
1996;
27
1993-1998
- 32
Scandinavian Simvastatin Survival Study Group .
Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease:
the Scandinavian Simvastatin Survival Study (4S).
Lancet.
1994;
344
1383-1389
- 33
Sacks F, Pfeffer M, Moye L A. et al .
The effect of pravastatin on coronary events after myocardial infarction in patients
with average cholesterol levels.
N Eng J Med.
1996;
335
1758-1764
- 34
White H D, Simes R J, Anderson N E. et al .
Pravastatin therapy and the risk of stroke.
N Engl J Med.
2000;
343
317-326
- 35
di Mascio R, Marchioli R, Tognoni G.
Cholesterol reduction and stroke occurence: an overview of randomized clinical trials.
Cerebrovasc Dis.
2000;
10
85-92
- 36
Byington R P, Davis B R, Plehn J F. et al .
Reduction of stroke events with pravastatin. The Prospective Pravastatin Pooling (PPP)
Project.
Circulation.
2001;
103
387-392
- 37
Sheperd J, Cobbe S M, Ford I. et al .
Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.
N Eng J Med.
1995;
333
1301-1307
- 38
Downs J R, Clearfield M, Weis S. et al .
Primary prevention of acute coronary events with lovastatin in men and women with
average cholesterol levels: results of the AFCAPS/TexCAPS. Air Force/Texas Coronary
Atherosclerosis Prevention Study.
JAMA.
1998;
179
1615-1622
- 39
MRC/BHF Heart protection Study Collaborative Group .
MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant
vitamin supplementation in a wide range of patients at increased risk of coronary
heart disease death: early safety and efficacy experience.
Eur Heart J.
1999;
20
725-741
- 40
Late Breaking Session American Heart Association. Heart Protection Study (HPS) .
Results - simvastatin.
Circulation.
2001;
Suppl I + II
104 (106 + 107)
- 41
Stroke prevention by aggressive reduction in cholesterol levels (SPARCL).
Stroke.
2000;
31
2541
- 42
Sheperd J, Blauw G J, Murphy M B. et al .
The design of a prospective study of pravastatin in the elderly at risk (PROSPER).
PROspective Study of Pravastatin in the Elderly at Risk.
Am J Cardiol.
1999;
84
1192-1197
- 43
Schwartz G, Olsson A G, Ezekowitz M D. et al .
Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes.
The MIRACL study: a randomized controlled trial.
JAMA.
2001;
285
1711-1718
- 44
Jonsson N, Asplund K.
Does pretreatment with statins improve clinical outcome after stroke? A pilot case-referent
study.
Stroke.
2001;
32
1112-1115
- 45
Treasure C B, Klein J L, Weintraub W S. et al .
Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in
patients with coronary artery disease.
N Eng J Med.
1995;
332
481-487
- 46
O'Driscoll G, Green D, Taylor R R.
Simvastatin, an HMG-Coenzyme A reductase inhibitor, improves endothelial function
within 1 month.
Circulation.
1997;
95
1126-1131
- 47
Vaughan C J, Delanty N, Basson C T.
Statin therapy and stroke prevention.
Curr Opn Cardiol.
2001;
16
219-224
- 48
Vaughan C J, Delanty N.
Neuroprotective properties of statins in cerebral ischemia and stroke.
Stroke.
1999;
30
1969-1973
- 49
Laufs U, Liao J K.
Direct vascular effects of HMG-CoA reductase inhibitors.
Trends Cardiovasc Med.
2000;
10
143-148
- 50
Libby P.
Molecular bases of the acute coronary syndromes.
Circulation.
1995;
91
2844-2850
- 51
Soma M R, Parolini C, Donetti E. et al .
Inhibition of isoprenoid biosynthesis and arterial smooth-muscle cell proliferation.
J Cardiovasc Pharmacol.
1995;
25, Suppl 4
S20-24
- 52
Munro E, Patel M, Chan P. et al .
Inhibition of human vascular smooth muscle cell proliferation by lovastatin: the role
of isoprenoid intermediates of cholesterol synthesis.
Eur J Clin Invest.
1994;
24
766-772
- 53
Llorente-Cortés V, Martínez-Gonzáles J, Badimon L.
Esterified cholesterol accumulation induced by aggregated LDL uptake in human vascular
smooth muscle cells is reduced by HMG-CoA reductase inhibitors.
Arterioscler Thromb Vasc Biol.
1998;
18
738-746
- 54
Bernini F, Scurati N, Bonfadini G, Fumagalli R.
HMG-CoA reductase inhibitors reduce acetyl LDL endocytosis in mouse peritoneal macrophages.
Arterioscler Thromb Vasc Biol.
1995;
15
1352-1358
- 55
Bellosta S, Via D, Canavesi M. et al .
HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages.
Arterioscler Thromb Vasc Biol.
1998;
18
1671-1678
- 56
Colli S, Eligini S, Lalli M. et al .
Vastatins inhibit tissue factor in cultured human macrophages: a novel mechanism of
protection against atherosclerosis.
Arterioscl Thromb Vasc Biol.
1997;
17
265-272
- 57
Crouse J R, Byington R P, Bond M G.
Pravastatin, lipids, and atherosclerosis in the carotid arteries (PLAC-II).
Am J Cardiol.
1995;
75
455-459
- 58
Furberg C D, Adams H P, Applegate W B. et al .
Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Asymptomatic
Carotid Artery Progression Study (ACAPS) Research Group.
Circulation.
1994;
90
1679-1687
- 59
Notarbartolo A, Davi G, Averna M.
Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type
IIa hypercholesterolemia.
Arteroscler Thromb Vasc Biol.
1995;
15
247-251
- 60
Davi G, Averna M, Novo S. et al .
Effects of synvinolin on platelet aggregation and thromboxane B2 synthesis in type
IIa hypercholesterolemia patients.
Atherosclerosis.
1989;
79
79-83
- 61
Cucchiara B, Kasner S E.
Use of statins in CNS disorders.
J Neurosci.
2001;
187
81-99
- 62
Ridker P M, Nader R, Lowenthal S P.
Rapid reduction in C-reactive protein with cerivastatin among 785 patients with primary
hypercholesterolemia.
Circulation.
2001;
103
1191-1193
- 63
Ridker P M, Rifai N, Clearfield M. et al .
Measurement of C-reactive Protein for the targeting of statin therapy in the primary
prevention of acute coronary events.
N Eng J Med.
2001;
344 (26)
1959-1965
- 64
Chen L, Haught W H, Yang B. et al .
Preservation of endogenous antioxidant activity and inhibition of lipid peroxidation
as common mechanisms of antiatherosclerotic effects of vitamin E, lovastatin and amlodipine.
J Am Coll Cardiol.
1997;
30
569-575
- 65
Hussein O, Schlezinger S, Rosenblat M. et al .
Reduced susceptibility of low density lipoprotein (LDL) to lipid peroxidation after
fluvastatin therapy is associated with hypocholesterolemic effect of the drug and
its binding to the LDL.
Atherosclerosis.
1997;
128
11-18
- 66
Endres M, Laufs U, Huang Z.
Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated
by endothelial nitric oxide synthase.
Proc Natl Acad Sci USA.
1998;
95
8880-8885
- 67
Clark R S, Kochanek P M, Schwarz M A. et al .
Inducible nitric oxide synthase expression in cerebrovascular smooth muscle and neutrophils
after traumatic brain injury in immature rats.
Pediatr Res.
1996;
39
784-790
- 68
Endoh M, Maiese K, Wagner J.
Expression of the inducible form of nitric oxide synthase by reactive astrocytes after
transient global ischemia.
Brain Res.
1994;
651
92-100
- 69
Pahan K, Sheikh F G, Namboodiri A MS, Singh I.
Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines
in rat primary astrocytes, microglia, and macrophages.
J Clin Invest.
1997;
100
2671-2679
- 70
Piser T M, Zacco A, Togo J A, Yancy A J.
Statins protect cultured mouse cortical neurons from NMDA-evoked excitotoxic death.
Soc Neurosci Abstr.
2000;
26
2283
- 71
Prince M, Cullen M, Mann A.
Risk factors for Alzheimer's disease and dementia: a case-control study based on the
MRC elderly hypertension trial.
Neurology.
1994;
44
97-104
- 72
Hofman A, Ott A, Breteler M M.
Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease
in the Rotterdam Study.
Lancet.
1997;
349
151-154
- 73
Jick H, Zomberg G L, Jick S S. et al .
Statins and the risk of dementia.
Lancet.
2000;
356
1627-1631
- 74
Wolozin B, Kellman W, Ruosseau P. et al .
Decreased prevalence of Alzheimer's disease associated with 3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitors.
Arch Neurol.
2000;
57
1439-1443
- 75 Scott H D, Laake K. Statins for the prevention of Alzheimer's disease (Cochrane
Review). In: The Cochrane Library 4. Oxford; Update Software 2001
- 76
Sparks D L.
Intraneuronal beta-amyloid immunoreactivity in the CNS.
Neurobiol Aging.
1996;
17
291-299
- 77
Sing C F, Davignon J.
Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein
variation.
Am J Hum Genet.
1985;
37
268-285
- 78
Fassbender K, Simons M, Bergmann C. et al .
Simvastatin strongly reduces levels of Alzheimer's disease β-amyloid peptides Aβ42
and Aβ40 in vitro and in vivo.
Proc Natl Acad Sci USA.
2001;
98
5856-5861
- 79
Frears E R, Stephens D J, Walters C E.
The role of cholesterol in the biosynthesis of beta-amyloid.
Neuroreport.
1999;
10
1699-1705
- 80
Simons M, Keller P, de Strooper B. et al .
Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons.
Proc Natl Acad Sci USA.
1998;
95
6460-6464
- 81
Prasanna P, Thibault A, Liu L, Samid D.
Lipid metabolism as a target for brain cancer therapy: synergistic activity of lovastatin
and sodium phenylacetate against human glioma cells.
J Neurochem.
1996;
66
710-716
- 82
Macaulay R J, Wang W, Dimitroulakos J.
Lovastatin-induced apoptosis of human medulloblastoma cell lines in vitro.
J Neurooncol.
1999;
42
1-11
- 83
Dimitroulakos J, Yeger H.
HMG-CoA reductase mediates the biological effects of retinoic acid on human neuroblastoma
cells: lovastatin specifically targets P-glycoprotein-expressing cells.
Nat Med.
1996;
2
326-333
- 84
Soma M R, Pagliarini P, Butti G. et al .
Simvastatin, an inhibitor of cholesterol biosynthesis, shows a synergistic effect
with N,N'-bis(2-cholorethyl)-N-nitrosourea and beta-inteferon on human glioma cells.
Cancer Res.
1992;
52
4348-4355
- 85
Kwak B, Mulhaupt F, Myit S, Mach F.
Statins as a newly recognized type of immunomodulator.
Nat Med.
2000;
6
1399-1402
- 86
Naderi S, Blomhoff R, Myklebust J. et al .
Lovastatin inhibits G1/S transition of normal human B-lymphocytes independent of apoptosis.
Exp Cell Res.
1999;
252
144-153
- 87
Hess D C, Demchuk A M, Brass L M. et al .
HMG-CoA reductase inhibitors (statins). A promising approach to stroke prevention.
Neurology.
2000;
54
790-796
- 88
Schatz I J, Masaki K, Yano K. et al .
Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program:
a cohort study.
Lancet.
2001;
358
351-355
- 89
Muldoon M F, Barger S D, Ryan C M. et al .
Effects of lovastatin on cognitive function and psychological well-being.
Am J Med.
2000;
108
538-646
- 90
Wardle J, Rogers P, Judd P, Taylor M A. et al .
Randomized trial of the effects of cholesterol-lowering dietary treatment on psychological
function.
Am J Med.
2000;
108
547-553
PD Dr. Matthias Endres
Klinik und Poliklinik für Neurologie · Charité · Humboldt-Universität zu Berlin
Schumannstraße 20/21
10098 Berlin
Email: matthias.endres@charite.de
