Dalcetrapib and anacetrapib differently impact HDL structure and function in rabbits and monkeys

Area of Science:

• Cardiovascular Research
• Pharmacology
• Lipid Metabolism

Background:

• Inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol (HDL-C).
• The impact of CETP inhibition on HDL structure and function in species with high CETP levels is not well understood.
• Dalcetrapib and anacetrapib are CETP inhibitors (CETPis) in clinical trials.

Purpose of the Study:

• To investigate the effects of dalcetrapib and anacetrapib on HDL particle subclass distribution and cholesterol efflux capacity.
• To compare the effects of these CETPis in rabbits and monkeys.

Main Methods:

• New Zealand White rabbits and vervet monkeys were treated with dalcetrapib and anacetrapib.
• HDL particle subclass distribution and cholesterol efflux capacity were measured.
• Changes in HDL-C and LDL-C levels were analyzed.

Main Results:

• In rabbits, CETPis increased HDL-C, altered HDL subclasses (α-migrating HDL), and enhanced ABCA1-induced cholesterol efflux.
• In vervet monkeys, anacetrapib showed similar effects to rabbits.
• Dalcetrapib in vervet monkeys paradoxically increased LDL-C and decreased HDL-C, reduced α- and preβ-HDL levels, and decreased cholesterol efflux capacity.

Conclusions:

• CETP inhibitors modulate plasma levels of mature and small HDL in vivo, affecting cholesterol efflux capacity.
• Dalcetrapib's opposing effects in different species suggest its impact on HDL metabolism is highly dependent on the metabolic environment.