Controversy on high density lipoprotein raising therapy.

Area of Science:

• Cardiovascular Pharmacology
• Lipid Metabolism Research

Background:

• Low high density lipoproteins (HDL) levels are linked to atherosclerotic cardiovascular disease.
• Pharmacological approaches to increase HDL cholesterol have been explored.
• Cholesteryl ester transfer protein (CETP) inhibition showed promise but faced challenges.

Purpose of the Study:

• To evaluate the potential of CETP inhibition in managing atherosclerotic cardiovascular disease.
• To understand the reasons behind the failure of early CETP inhibitors like torcetrapib.
• To explore the development of safer and more effective CETP inhibitors.

Main Methods:

• Review of clinical trial data for torcetrapib.
• Analysis of HDL structure, heterogeneity, and functions beyond reverse cholesterol transport.
• Investigation of torcetrapib's off-target effects, including effects on plasma electrolytes.
• Elucidation of CETP structure to guide the design of new inhibitors.

Main Results:

• Torcetrapib increased mortality and did not prevent atherosclerosis progression.
• Torcetrapib's adverse effects were linked to its binding to CETP and off-target actions (aldosterone-like effect).
• CETP deficiency in animal models (mice, rats) confers resistance to atherosclerosis, while high CETP levels in rabbits increase susceptibility.

Conclusions:

• CETP inhibition remains a viable strategy for treating atherosclerosis, provided off-target toxicity is avoided.
• Designing CETP inhibitors based on structural insights can mitigate adverse effects.
• Further research into CETP inhibitors holds potential for developing novel therapies for cardiovascular disease.