CETP-inhibitor reduces non-HDL-cholesterol via reducing PCSK9 and enhancing hepatic remnant clearance
Anacetrapib reduces (V)LDL-cholesterol via reducing PCSK9 and enhancing hepatic remnant clearancePresented by: Yanan Wang (Leiden, The Netherlands)
New insights on the mechanism via which the CETP-inhibitor anacetrapib reduces non-HDL-c, were presented today at the 17th International Symposium on Atherosclerosis, May 23-26, 2015, Amsterdam, The Netherlands.
HDL-C is strongly associated with reduced risk of cardiovascular disease (CVD) and compounds to increase HDL-C are actively being pursued as novel drugs to reduce CVD. One class of HDL-C raising compounds is aimed at inhibiting Cholesteryl Ester Transfer Protein (CETP). Thus far, two CETP inhibitors have failed in clinical trials mainly due to futility. A third CETP inhibitor, anacetrapib, is currently being evaluated in phase III clinical trials.
A recent study from Yanan Wang and colleagues at Leiden University Medical Center and TNO-Metabolic Health Research showed that, in a mouse model with a human-like lipoprotein metabolism, anacetrapib decreased atherosclerosis development on top of conventional statin treatment, which was surprisingly only explained by a reduction in non-HDL-C (Eur Heart J 2015).
The investigators now study the mechanism by which anacetrapib reduces non-HDL-C. Using the humanized mouse model, the authors report that anacetrapib does not inhibit the production of non-HDL-C, but increases the clearance of non-HDL-C via enhancing the remnant uptake by liver. Further investigation revealed that anacetrapib reduces the plasma PCSK9 level and increases hepatic LDL-receptor protein independent of CETP inhibition.
According to the authors, the results from this study may have clinical implications. They propose that anacetrapib may decrease CVD on top of conventional statin treatment by further reducing non-HDL-C via decreasing PCSK9 and enhancing hepatic remnant clearance.