Dalcetrapib: a review of Phase II data

Area of Science:

• Cardiovascular disease research
• Pharmacology of lipid-modulating agents
• Cholesteryl ester transfer protein (CETP) inhibition

Background:

• Statins effectively reduce cardiovascular disease (CVD) risk but leave many patients with residual risk due to low high-density lipoprotein cholesterol (HDL-C).
• The therapeutic benefit of pharmacologically increasing HDL-C levels remains uncertain.

Purpose of the Study:

• To review HDL-C-raising compounds, specifically focusing on CETP inhibitors.
• To provide an overview of the CETP inhibitor dalcetrapib and its potential role in managing cardiovascular risk.

Main Methods:

• Review of existing literature on HDL-C-raising compounds.
• Focus on the mechanism of action, clinical effects, and safety profile of CETP inhibitors, particularly dalcetrapib.
• Analysis of data from clinical trials, including surrogate endpoint studies and outcome trials.

Main Results:

• Development of some CETP inhibitors (e.g., torcetrapib) was halted due to safety concerns, including increased mortality and hypertension.
• Dalcetrapib exhibits a unique mechanism, inducing a conformational change in CETP without forming non-productive complexes.
• Dalcetrapib at a 600-mg dose raises HDL-C by 25-30% with minimal impact on low-density lipoprotein cholesterol (LDL-C) and without increasing blood pressure or aldosterone levels.

Conclusions:

• The ongoing dal-OUTCOMES trial is crucial for evaluating dalcetrapib's efficacy in reducing mortality and morbidity in high-risk patients with coronary heart disease (CHD).
• The dal-HEART program's surrogate endpoint trials (dal-VESSEL, dal-PLAQUE, dal-PLAQUE 2) will further elucidate CETP's role in cardiovascular disease progression.