Targeting high density lipoproteins in the prevention of cardiovascular disease?

Area of Science:

• Cardiovascular Medicine
• Pharmacology
• Biochemistry

Background:

• High-density lipoprotein cholesterol (HDL-C) raising therapeutics have evolved significantly.
• Niacin, despite raising HDL-C, has uncertain clinical benefits.
• Previous HDL-raising drug candidates, including niacin receptor agonists and some CETP inhibitors, have shown limited efficacy or faced development challenges.

Purpose of the Study:

• To review the current landscape of HDL-raising therapeutics.
• To discuss the transition from the HDL-cholesterol hypothesis to the HDL flux hypothesis.
• To highlight emerging therapeutic strategies targeting HDL metabolism and function.

Main Methods:

• Review of recent clinical trial data and preclinical studies on HDL therapeutics.
• Analysis of novel drug targets and mechanisms of action.
• Discussion of the evolving understanding of HDL's role in cardiovascular disease.

Main Results:

• Several novel HDL therapeutics, including CETP inhibitors, recombinant HDL infusions, and apoA-I modulators, are in late-stage development.
• Upregulation of endogenous apoA-I production and enhancement of macrophage cholesterol efflux pathways are promising strategies.
• Early clinical data for some novel agents show significant impact on HDL-C and LDL-C levels, and cholesterol efflux.

Conclusions:

• The field of HDL therapeutics is moving beyond simply increasing HDL-C concentrations.
• The focus is shifting towards improving cholesterol efflux and flux, reflecting the 'HDL flux hypothesis'.
• Emerging therapies hold promise for improved cardiovascular outcomes by targeting these novel pathways.