Torcetrapib Differentially Modulates the Biological Activities of HDL2 and HDL3 Particles in the Reverse Cholesterol Transport Pathway
Objective— Therapeutic strategies to raise low plasma HDL-cholesterol levels, with concomitant normalization of the intravascular metabolism, physicochemical properties, and antiatherogenic function of HDL particles, are a major focus in atherosclerosis prevention.
Methods and Results— Patients displaying Type IIB hyperlipidemia (n=14) and healthy controls (n=11) were recruited. After drug washout, dyslipidemic patients first received atorvastatin (10 mg/d) for 6 weeks and subsequently torcetrapib/atorvastatin (60/10 mg/d) for the same period. Partial CETP inhibition markedly reduced supranormal CE transfer rates to normal levels from HDL3 (−58%; P<0.0001) to apoB-lipoproteins; endogenous CE transfer rates from HDL2 to apoB-lipoproteins were markedly subnormal as compared to those in control subjects (10.7±0.9 versus 29.3±4.8 μgCE/h/mL plasma, respectively). Torcetrapib enhanced the subnormal capacity of HDL2 particles from dyslipidemic patients to mediate free cholesterol efflux via both SR-BI and ABCG1 pathways (+38%;P<0.003 and +35%;P<0.03, respectively) as compared to baseline. In vitro observations and in vivo studies in mice demonstrated that CETP inhibition was associated with an enhanced selective hepatic uptake of CE from HDL particles (1.7-fold; P<0.0003).
Conclusion— CETP inhibition partially corrected the abnormal physicochemical and functional properties of HDL2 and HDL3 particles in type IIB hyperlipidemia. Enhanced hepatic selective uptake of HDL-CE may compensate for attenuated indirect CE transfer to apoB-containing lipoproteins via CETP attributable to torcetrapib.