Review finds anacetrapib and dalcetrapib safely raise HDL-C without the off-target effects that doomed torcetrapib (Ann Pharmacother 2011)

Objective: To evaluate the role of cholesteryl ester transfer protein (CETP) in the cholesterol transport system and review the pharmacology, pharmacokinetic properties, efficacy, and adverse effects of the CETP inhibitors, anacetrapib and dalcetrapib, for the treatment of dyslipidemia.

Data Sources: A literature search was conducted in Ovid/MEDLINE (1950 to week 4 December 2010), PubMed/MEDLINE (up to December 2010), EMBASE (2000 to December 2010), and International Pharmaceutical Abstracts (1970 to December 2010) using the MeSH terms and key words anacetrapib, MK 0859, dalcetrapib, and JTT 705. The search was limited to publications in English.

Study Selection And Data Extraction: Studies evaluating the pharmacology, pharmacokinetics, safety, and efficacy of anacetrapib and dalcetrapib for the treatment of dyslipidemia were included. Clinical reviews evaluating the characterization of CETP and its inhibition as a mechanism for reducing cardiovascular risk were also included.

Data Synthesis: Anacetrapib and dalcetrapib represent a novel treatment option for patients who have dyslipidemia and low levels of high-density lipoprotein cholesterol (HDL-C). Anacetrapib and dalcetrapib increase HDL-C by inhibiting CETP-mediated transfer of cholesteryl ester and triglyceride. Studies evaluating the safety and efficacy of anacetrapib and dalcetrapib concluded that both agents safely and effectively augment HDL-C. Their mechanism of action, potential for significant raising of HDL-C, once-daily dosing regimen, and favorable lipid-altering effects when added to hydroxymethylglutaryl-CoA reductase inhibitors are key elements. Anacetrapib and dalcetrapib are well tolerated, with mild gastrointestinal complaints reported more than with placebo. Although another CETP inhibitor, torcetrapib, was withdrawn from clinical development secondary to increased morbidity and mortality, neither anacetrapib nor dalcetrapib has demonstrated the adverse off-target effects portrayed with torcetrapib.

Conclusions: Inhibition of CETP by anacetrapib and dalcetrapib represents an encouraging development in the management of dyslipidemia, particularly in patients with low HDL-C levels. Results of future trials are much anticipated, as these will clarify the role of anacetrapib and dalcetrapib in reduction of cardiovascular disease.