HDL – Quo vadis

Niedrige Plasmaspiegel von HDL-Cholesterin (HDL-C) sind in epidemiologischen Studien mit einem erhöhten Risiko für atherosklerotische kardiovaskuläre Erkrankungen (ASCVD) assoziiert. In Zellkultur- und Tiermodellen üben HDL-Partikel potenziell antiatherogene Wirkungen aus. Alle bisher getesteten Medikamente zur HDL-C-Erhöhung waren nicht in der Lage, zusätzlich zu Statinen kardiovaskuläre Ereignisse zu verhüten. Auch Ergebnisse genetischer Studien stellten die kausale Rolle von für ASCVD in Frage. Allerdings reflektiert HDL-C nicht die Funktionalität von HDL-Partikeln.

Abstract

Many epidemiological studies found low plasma levels of high-density lipoprotein (HDL) cholesterol (HDL-C) associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). In cell culture and animal models, HDL particles show many anti-atherogenic actions. However, until now, clinical trials did not find any prevention of ASCVD events by drugs elevating HDL-C levels, at least not beyond statins. Also, genetic studies show no associations of HDL-C levels altering variants with cardiovascular risk. Therefore, the causal role and clinical benefit of HDL-C elevation in ASCVD are questioned. However, the interpretation of previous data has important limitations: First, the inverse relationship of HDL-C with the risk of ASCVD is limited to concentrations < 60 mg/dl (< 1.5 mmol/l). Higher concentrations do not reduce the risk of ASCVD events and are even associated with increased mortality. Therefore, neither the higher-the-better strategies of earlier drug developments nor the assumption of linear cause-and-effect relationships in Mendelian randomization trials are justified. Second, most of the drugs tested so far do not act specifically on HDL metabolism. Therefore, the futile endpoint studies question the clinical benefit of the investigated drugs, but not the importance of HDL in ASCVD. Third, the vascular functions of HDL are not exerted by its cholesterol content (i.e. HDL-C), but by a variety of other molecules. Comprehensive knowledge of the structure-function-disease relationships of HDL particles and their molecules is a prerequisite for testing their physiological and pathogenic relevance and possibly for optimizing the diagnosis and treatment of persons with HDL-associated risk of ASCVD, but also for other diseases, such as diabetes, chronic kidney disease, infections, autoimmune and neurodegenerative diseases.

Kernaussagen

• Niedriges HDL-C ist ein Risikomarker; hohes HDL-C ist nicht protektiv; der HDL/LDL-Quotient ist obsolet.

• Eine lebensstilassoziierte HDL-C-Erhöhung durch Nichtrauchen und körperliche Aktivität ist mit einer Reduktion von ASCVD assoziiert.

• HDL-C ist, anders als LDL-C oder Non-HDL-C, kein Ziel für medikamentöse Therapien zur Reduktion des ASCVD-Risikos.

• Aktuelle Forschungsergebnisse zur Bestimmung der HDL-Funktion sind interessant, aber aktuell noch ohne klinische Konsequenz.

• Dasselbe gilt für die epidemiologischen und genetischen Beziehungen von HDL-C zu nicht kardiovaskulären Erkrankungen.

Schlüsselwörter

HDL - Atheroskerose - Risikofaktor - Biomarker - Lipoprotein

Keywords

HDL - atherosclerosis - risk factor - biomarker - lipoprotein

Publication History

Article published online:
20 April 2023

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