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Low high-density lipoprotein cholesterol: physiological background, clinical importance and drug treatment
Martin Hersberger1, Arnold von Eckardstein
1Institute of Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland.
Insights
Low high-density lipoprotein (HDL) cholesterol increases coronary heart disease risk. Simply raising HDL cholesterol may not be effective; modifying HDL function is key for anti-atherosclerotic therapy.
Area of Science:
- Cardiovascular Medicine
- Lipid Metabolism
- Pharmacology
Background:
- Low high-density lipoprotein (HDL) cholesterol is a significant risk factor for coronary heart disease (CHD).
- HDL possesses multiple anti-atherogenic properties, including reverse cholesterol transport (RCT), inhibition of LDL oxidation, and modulation of endothelial cell function.
- Raising HDL cholesterol levels is a therapeutic target for anti-atherosclerotic drug development.
Purpose of the Study:
- To review the role of HDL cholesterol in cardiovascular health.
- To evaluate the efficacy of current therapies targeting HDL cholesterol.
- To explore novel strategies for modifying HDL metabolism and function.
Main Methods:
- Review of in vitro studies on HDL functionality.
- Analysis of clinical intervention studies with fibrates, statins, nicotinic acid, and sex steroids.
- Discussion of genetic models and inborn errors of metabolism affecting HDL levels.
Main Results:
- Elevated HDL cholesterol does not always correlate with reduced cardiovascular risk, suggesting HDL function is critical.
- Current drugs (fibrates, statins) show moderate increases in HDL cholesterol, with variable impact on cardiovascular events.
- The correlation between increased HDL cholesterol and prevention of coronary events is inconsistent, particularly in patients with hypertriglyceridemia.
Conclusions:
- Modification of HDL metabolism and improvement of RCT are promising targets for future anti-atherosclerotic therapies.
- Current anti-atherosclerotic therapy for high-risk patients should prioritize addressing other risk factors alongside low HDL cholesterol.
- Simply increasing HDL cholesterol levels may not be sufficient; enhancing HDL functionality is crucial for therapeutic efficacy.
Abstract:
Low high-density lipoprotein (HDL) cholesterol is an important risk factor for coronary heart disease (CHD). In vitro, HDL exerts several potentially anti-atherogenic activities. HDLs mediate the reverse cholesterol transport (RCT) from peripheral cells to the liver, inhibit oxidation of low-density lipoprotein (LDL), adhesion of monocytes to the endothelium, apoptosis of vascular endothelial and smooth muscle cells and platelet activation, and stimulate the endothelial secretion of vasoactive substances as well as smooth muscle cell proliferation. Hence, raising HDL-cholesterol levels has become an interesting target for anti-atherosclerotic drug therapy. Levels of HDL cholesterol and the composition of HDL subclasses in plasma are regulated by apolipoproteins, lipolytic enzymes, lipid transfer proteins, receptors and cellular transporters. The interplay of these factors leads to RCT and determines the composition and, thereby, the anti-atherogenic properties of HDL. Several inborn errors of metabolism, as well as genetic animal models, are characterised by both elevated HDL cholesterol and increased rather than decreased cardiovascular risk. These findings suggest that the mechanism of HDL modification rather than simply increasing HDL cholesterol determine the efficacy of anti-atherosclerotic drug therapy. In several controlled and prospective intervention studies, patients with low HDL cholesterol and additional risk factors benefited from treatment with fibric acid derivatives (fibrates) or HMG-CoA reductase inhibitors (statins). However, only in some trials was prevention of coronary events in patients with low HDL cholesterol and hypertriglyceridaemia related to an increase in HDL cholesterol. We discuss the clinical and metabolic effects of fibrates, statins, nicotinic acid and sex steroids, and present novel therapeutic strategies that show promise in modifying HDL metabolism. In conclusion, HDL-cholesterol levels increase only moderately after treatment with currently available drugs and do not necessarily correlate with the functionality of HDL. Therefore, the anti-atherosclerotic therapy of high-risk cardiovascular patients should currently be focused on the correction of other risk factors present besides low HDL cholesterol. However, modification of HDL metabolism and improvement of RCT remain an attractive target for the development of new regimens of anti-atherogenic drug therapy.