The continuing complexities of high-density lipoprotein metabolism in drug discovery and development

Area of Science:

• Cardiovascular Research
• Pharmacology
• Drug Development

Background:

• The Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events (ILLUMINATE) trial for Pfizer's CETP inhibitor torcetrapib was terminated due to increased mortality.
• This event has significant implications for drug discovery targeting high-density lipoprotein (HDL) and atherosclerosis.

Discussion:

• While torcetrapib's failure reasons remain unclear, its impact on the field is evident.
• Imaging studies showed no change in lesion size, offering some interpretational confidence.
• The established rationale for raising HDL is strong, but new mechanisms will face increased scrutiny.

Key Insights:

• Torcetrapib's trial termination raises critical questions for HDL-targeting drug development.
• Despite strong evidence for raising HDL, new therapeutic strategies will undergo more rigorous evaluation.
• Existing HDL-modifying drugs, like niacin, are being re-evaluated in light of these developments.

Outlook:

• Expect longer development timelines for drugs targeting novel mechanisms in atherosclerosis.
• Future research will likely focus on re-evaluating existing HDL-modifying therapies.
• The field must adapt to increased scrutiny following the torcetrapib trial outcome.