The end of the road for CETP inhibitors after torcetrapib?

Area of Science:

• Cardiovascular Research
• Pharmacology
• Metabolic Diseases

Background:

• High-density lipoprotein cholesterol (HDL-C) is inversely associated with cardiovascular disease (CVD) risk.
• The failure of torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, to reduce CVD incidence has cast doubt on HDL-C-raising strategies.
• CETP inhibition is a mechanism explored for modulating HDL-C levels and potentially preventing atherosclerosis.

Purpose of the Study:

• To review the complexity of HDL metabolism and the implications of CETP inhibition for CVD prevention.
• To discuss the potential reasons for torcetrapib's failure in clinical trials.
• To evaluate the prospects of alternative CETP inhibitors.

Main Methods:

• Review of existing literature on HDL metabolism, CETP inhibition, and clinical trial outcomes.
• Analysis of the pharmacological properties and clinical data of torcetrapib, dalcetrapib, and anacetrapib.
• Discussion of potential off-target effects and mechanisms of action.

Main Results:

• Torcetrapib's failure may be attributed to off-target effects, specifically a CETP-independent pressor effect (increased blood pressure).
• Other CETP inhibitors, anacetrapib and dalcetrapib, have not shown similar pressor effects in early human trials.
• Preliminary data suggest anacetrapib and dalcetrapib can improve lipoprotein profiles without apparent short-term adverse effects.

Conclusions:

• Further research is needed to clarify the relationship between HDL metabolism, CETP inhibition, and atherosclerosis.
• Cautious continuation of clinical evaluation for CETP inhibitors like dalcetrapib and anacetrapib is warranted.
• It remains uncertain if torcetrapib's adverse outcomes were agent-specific or related to CETP inhibition as a general CVD prevention strategy.