Zusammenfassung
Auch bei leitliniengerechter Behandlung erhöhter „Low
Density Lipoprotein” (LDL)-Cholesterin-Konzentrationen
können zahlreiche kardiovaskuläre Ereignisse nicht
verhindert werden. Ein möglicher Ansatz zur Senkung des
verbleibenden Risikos ist die medikamentöse Steigerung des „High
Density Lipoprotein” (HDL)-Cholesterins. Epidemiologische
Studien zeigen, dass die HDL-Konzentration im Plasma invers mit
dem Auftreten kardiovaskulärer Ereignisse korreliert. Unter
physiologischen Bedingungen vermittelt HDL den reversen Cholesterintransport
und ist vaskuloprotektiv. Neue Studien weisen jedoch darauf hin,
dass HDL-Partikel unter pathophysiologischen Umständen
auch Atherosklerose begünstigen könnten. Interventionsstudien
und Meta-Analysen, die den Effekt einer medikamentösen
HDL-Steigerung auf das kardiovaskuläre Risiko untersuchten,
zeigen bislang keine eindeutigen Ergebnisse.
Die Hemmung des Cholesterylester-Transferproteins (CETP) ist
eine neue Strategie zur Erhöhung der HDL-Konzentration.
Die Therapie mit dem CETP-Hemmer Torcetrapib erhöhte die
HDL-Konzentration zwar wesentlich, hatte jedoch auch einen substanzspezifischen
Blutdruckanstieg zur Folge, der mit vermehrten klinischen Ereignissen
einherging. Diese Effekte sind für die neueren CETP-Hemmer
wie Dalcetrapib und Anacetrapib nicht bekannt und werden auch bei der
genetischen CETP-Defizienz nicht beobachtet. Eine Steigerung der
HDL-Plasmakonzentration muss nicht automatisch eine Verbesserung der
HDL-Funktion und einen effektiven Cholesterinrücktransport
bedeuten. Eine wichtige offene Frage bleibt daher die funktionelle
Charakterisierung der unter CETP-Modulation generierten HDL-Partikel
und die Evaluation der biliären Cholesterinausscheidung.
Laufende klinische Studien (z. B. Dal-Heart) mit den neueren
CETP-Hemmern werden zeigen, ob eine Erhöhung der HDL-Konzentration
durch eine CETP-Hemmung kardiovaskuläre Ereignisse reduziert.
Abstract
Despite optimal treatment of high low density lipoprotein (LDL) cholesterol
with statins many cardiovascular events are not prevented. Additional
therapeutic strategies are required to reduce the residual cardiovascular
risk. Large epidemiological studies show an inverse correlation
between the plasma concentration of high density lipoprotein (HDL)
cholesterol and the incidence of cardiovascular events. Under physiological
conditions, HDL is vasculoprotective and mediates the reverse cholesterol
transport. However, new studies suggest that HDL particles represent a
heterogeneous population. Under several pathophysiological conditions,
HDL was shown to promote atherogenesis and inflammation. Interventional
studies and metaanalyses examining the effect of increasing HDL
cholesterol have reported mixed results. Inhibition of cholesteryl
ester transfer protein (CETP) is a new and potent strategy to increase
HDL concentrations. However, the first CETP-inhibitor torcetrapib
increased blood-pressure and increased cardiovascular events despite
increasing HDL. The blood-pressure increasing effects are not known
for more recently developed CETP inhibitors such as dalcetrapib
and anacetrapib nor in patients with genetic CETP deficiency. An
increase of HDL cholesterol does not necessarily imply an improvement
of the functional properties of HDL such as reverse cholesterol
transport. An important open question remains the functional characterization
of HDL generated by CETP inhibition. Important current clinical
endpoint studies with new CETP inhibitors will elucidate whether
increasing HDL by CETP inhibition leads to a reduction of cardiovascular
events.
Schlüsselwörter
Lipidstoffwechsel - HDL - CETP - Statine
Keywords
lipid metabolism - HDL - CETP - statins
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Dr. med. Janine Pöss
Klinik für Innere Medizin III, Kardiologie,
Angiologie und Internistische Intensivmedizin, Universitätsklinikum
des Saarlandes
66424 Homburg/Saar
Phone: 06841/1623436
Fax: 06841/1623434
Email: janine.poess@gmx.de