Abstract 118: The Effect of CETP Inhibition With Anacetrapib on the Metabolism of PCSK9
Introduction Inhibition of CETP activity with anacetrapib has been associated with a significant reduction in low density lipoprotein (LDL)-cholesterol (C) levels both as a monotherapy and in combination with a statin. We recently reported that this reduction in LDL-C is due to a significant increase in the fractional clearance rate (FCR) of LDL apoB. One potential mechanism by which anacetrapib could influence LDL apoB clearance is through effects on PCSK9 metabolism. We conducted kinetic studies on PCSK9 to determine if a change in the metabolism of PCSK9 is responsible for the reduction in LDL-C levels following treatment with anacetrapib.
Methods Moderately hyperlipidemic volunteers (n=39) were enrolled in a fixed-sequence study: 75% were on atorvastatin (20mg/day) plus placebo and 25% were on double placebo for four weeks. Following this baseline period subjects added anacetrapib (100 mg/day) to their background treatment for 8 weeks. Studies using D3 leucine tracer were performed at the end of each treatment period to determine the kinetics PCSK9.
Results Statin treated subjects had lower LDL-C levels (84 vs 118 mg/dL) and higher PCSK9 levels (234 vs. 208 ng/mL) at baseline than subjects on placebo. The difference in PCSK9 was due to a higher PCSK9 production rate (PR) (19.7 vs. 16.7 ug/kg/day) but similar PCSK9 FCR (1.87 vs. 1.78 pools/day). Adding anacetrapib to background treatment was associated with a significant reduction in LDL cholesterol (~ -35%) and apoB levels (~ 20%) in both panels. Anacetrapib had no significant effect on PCSK9 levels in either of the background treatment groups. Consistent with the lack of change in PCSK9 levels, there was no effect of anacetrapib on the PR (18.1 vs. 19.3 ug/kg/day) or FCR of PCSK9 (1.82 vs. 1.93 pools/day).
Conclusion These results indicate that in our study population the increase in LDL FCR observed in response to anacetrapib treatment is not likely to be related to changes in the metabolism of PCSK9.
- © 2013 by American Heart Association, Inc.