HDL im Rahmen der Atherogenese und HDL-Steigerung durch CETP-Inhibition

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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