Revising the high-density lipoprotein targeting strategies - insights from human and preclinical studies

Area of Science:

• Cardiovascular Medicine
• Lipid Metabolism
• Pharmacology

Background:

• The high-density lipoprotein (HDL) hypothesis, linking HDL-cholesterol (HDL-C) levels to cardiovascular disease (CVD) prevention, is increasingly challenged.
• Recent clinical trials have failed to consistently demonstrate HDL-C as a viable therapeutic target for CVD prevention.
• Despite trial outcomes, epidemiological studies and lipid-modifying trials continue to support HDL-C as a significant predictor of cardiovascular risk.

Purpose of the Study:

• To critically evaluate the current understanding of the HDL hypothesis in light of recent clinical trial data.
• To explore the complexities of HDL metabolism and their implications for targeting HDL-C.
• To identify emerging insights from recent trials and mechanistic studies to guide future HDL-based therapeutic strategies.

Main Methods:

• Post hoc analyses of completed randomized clinical trials, including fibrate-based (FIELD, ACCORD), niacin-based (AIM-HIGH, HPS2-THRIVE), recombinant HDL, and CETP inhibitor trials.
• Review of ongoing mechanistic studies investigating novel pathways in HDL metabolism.
• Examination of the roles of microRNAs, post-translational HDL remodeling, and novel HDL modulators.

Main Results:

• Fibrate-based trials showed unexpected benefits in microvascular diseases.
• Niacin-based studies provided insights into HDL function beyond cholesterol levels.
• CETP inhibitor trials and recombinant HDL studies offered further data on HDL's complex role in cardiovascular health.

Conclusions:

• The concentration of HDL-C alone is insufficient as a unified therapeutic target due to the intricate nature of HDL metabolism.
• Emerging research on microRNAs, HDL remodeling, and novel modulators offers new avenues for understanding and targeting HDL.
• A refocused conceptual framework is needed to effectively select HDL-based targets for cardiovascular disease prevention.