Abstract 235: Atorvastatin Has No Impact on the Effects of CETP Inhibitors on HDL Structure and Cholesterol Efflux Capacity in Chow-Fed Rabbits
Introduction: In the dal-OUTCOMES trial, cholesteryl ester transfer protein (CETP) inhibition by dalcetrapib increased HDL-C but had a neutral effect on CV risk. However, these patients were also treated with standard-of-care therapies including statins, a drug class shown to reduce ABCA1 mRNA expression in human peripheral blood mononuclear cells (PBMC).
Hypothesis: Given the role of ABCA1 in cholesterol efflux and HDL biogenesis, we determined the impact of atorvastatin on the potential beneficial effects provided by dalcetrapib and anacetrapib, two CETP inhibitors.
Methods: Dalcetrapib (300 mg/kg) or anacetrapib (30 mg/kg) were administered to New Zealand White rabbits receiving or not atorvastatin (2.5 mg/kg) for 14 days. Lipid profiles were measured biochemically. ApoA-I distribution in HDL subclasses was evaluated by 1D-non-denaturing gradient gel electrophoresis (1D-NDGGE). BHK cells with inducible expression of human ABCA1 and HepG2 hepatocytes were used to measure ABCA1- and SR-BI-dépendent cholesterol efflux. Human THP-1 macrophages and PBMC isolated from rabbits were also used for efflux assays.
Results: Dalcetrapib increased HDL-C by +81% (p<0.01) and total apoA-I (1D-NDGGE) by 1.5-fold (p<0.01). This was associated with an increase in both large and small α-migrating HDL (+52%, p<0.05; +74%, p<0.05). Cholesterol efflux showed that ABCA1- and SR-BI-dependent effluxes to apoB-depleted serum were increased in dalcetrapib-treated rabbits (+31%, p<0.01; +38%, p<0.001). Atorvastatin had no impact on all these parameters. Moreover, treatment of THP-1 with atorvastatin did not inhibit the increase of cholesterol efflux (+24%, p<0.01) induced by depleted serum from dalcetrapib-treated rabbits. Efflux capacity of PBMC isolated from rabbits treated with atorvastatin was also unchanged compared to the other groups. The absence of effect of atorvastatin on cholesterol efflux was also observed with anacetrapib.
Conclusion: CETP inhibition increased HDL-C, apoA-I levels and cholesterol efflux from different cell types. Atorvastatin had no effect on these parameters, suggesting that the increased cholesterol efflux capacity induced by CETPi is not hampered by statins.
Author Disclosures: M.R. Brodeur: None. D. Rhainds: None. D. Charpentier: None. T. Mihalache-Avram: None. M. Mecteau: None. G. Brand: None. C. Maugeais: Employment; Significant; F. Hoffmann-La Roche. E.J. Niesor: Employment; Significant; F. Hoffmann-La Roche. E. Rhéaume: None. J. Tardif: Research Grant; Significant; F. Hoffmann-La Roche.
- © 2014 by American Heart Association, Inc.