Abstract 13635: CETP Inhibitor (Torcetrapib) Induces LDL Particle Polydispersity Like that Observed in CETP Deficient Homozygote Subjects
Background: LDL subclass distribution may be correlated with CVD risk. An advantage of gradient gel electrophoresis (GGE) is that it gives a visual image of the subfractions. This report is the first to present an unusual GGE-derived LDL subclass pattern resulting from CETP inhibitor treatment with torcetrapib.
Methods: Plasma samples were obtained from 1) subjects who participated in Ph 2 protocols from the Pfizer torcetrapib clinical studies conducted between 2001 and 2003 and were treated with torcetrapib alone, torcetrapib plus atorvastatin or atorvastatin alone; and 2) homozygous CETP deficient subjects (Intron 14 A). LDL and HDL particles were separated simultaneously using 2-30% polyacrylamide non-denaturing GGE.
Results: In comparison to untreated historic controls, which display a major band and a minor band(s), the LDL pattern of torcetrapib-treated plasma, exhibited LDL-band polydispersity with an increased number of discrete bands that cover a significantly wider range of size distribution that exceeds the size limits used in standard algorithms for subfraction calculation. This pattern, observed as early as week 4 on torcetrapib 60 mg BID, was similar to that seen in CETP-deficient homozygote plasma. The polydispersed pattern was not affected by co-administration of atorvastatin. Atorvastatin increased the major LDL particle size and decreased LDL-C but did not itself induce LDL particle polydispersity.
Conclusions: Torcetrapib induced a polydispersed LDL particle pattern, similar to that observed in CETP deficient homozygote subjects. This pattern is not observed in untreated or atorvastatin treated subjects. Whether or not the torcetrapib-induced polydispersed LDL pattern is seen with other CETP inhibitors in late-stage clinical trials is unknown. Implications of the polydispersed LDL size pattern on clinical efficacy remain to be elucidated and detection of the phenomena currently requires GGE. SPAN>
- © 2011 by American Heart Association, Inc.