Cholesteryl Ester Transfer Protein Inhibition With Anacetrapib Increases Fractional Clearance Rates of High-Density Lipoprotein Apolipoprotein A-I and Plasma Cholesteryl Ester Transfer Protein

Reyes-Soffer G, Millar JS, Ngai C, et al.
Arterioscler Thromb Vasc Biol. 2016;36:published online ahead of print

Background

It has been shown that LDL-C-lowering therapy with statins decreases the risk of CVD events, but it is unclear whether the same result can be achieved by increasing HDL-C with CETP inhibition [1,2]. Relevant studies have come to the following conclusions:

• ILLUMINATE study: torcetrapib increased HDL-C by 60% - 100% but actually increased CVD events [3]
• dal-OUTCOMES study: dalcetrapib increased HDL-C by approximately 30% and had no effect on CVD events [4]
• ACCELERATE study: evacetrapib was stopped early because of insufficient efficacy on outcome endpoints [5]

The existing data raise questions regarding the pharmacological effects of CETP inhibition on reverse cholesterol transport [6]. Moreover, there is evidence with limited power, suggesting that the addition of atorvastatin to the CETP inhibitor torcetrapib, negates the torcetrapib benefits on the fractional clearance rate of apoA-I from plasma [7].
In the meantime, anacetrapib (ANA), another CETP inhibitor under development that increases HDL-C by up to 140% [8], is currently tested in the CVD outcomes study REVEAL [9].
The present randomised, placebo-controlled, double-blind study investigated the effects of ANA on the metabolism of HDL apoA-I and apoA-II and plasma CETP, with or without atorvastatin (ATV) therapy, in 39 individuals.

Main results

In the ATV-ANA group, 8 weeks of ANA treatment on a statin background resulted in:

• an increase in HDL-C (68.1%; P<0.001)
• a decrease in LDL-C (38.0%; P<0.001)
• no changes in TG
• increased plasma apoA-I concentrations (29.3%; P<0.001)
• increased apoA-II levels (11.9%; P<0.001)

In the PBO-ANA group:

• HDL-C increased (53.5%; P=0.055)
• LDL-C decreased (34.5%; P=0.039)
• TG levels decreased (24.5%; P=0.012)
• plasma apoA-I concentrations increased (29.7%; P<0.001)
• apoA-II levels increased (13.3%; P=0.008)

The increase in apoA-I pool size during ANA treatment was driven by a significant decrease in the HDL apoA-I fractional clearance rates (15.7% in the ATV-ANA and 20.7% in the PBO-ANA group; P=0.009 and P=0.029, respectively), without changes in the production rate. Importantly, the reductions in the fractional turnover of apoA-I were associated with an increase in both pre-β and larger α HDL subfractions. No significant changes in either apoA-II fractional clearance rate or production rate could be observed.  
• The cholesterol content in isolated HDL after ultracentrifugation increased:

• by 85.2% in the ATV-ANA group (P<0.001)
• by 97.8% in the PBO-ANA group (P<0.001)

Cholesteryl ester, which accounted for >80% of the total cholesterol content in the HDL fractions, increased:

• by 81.0% in the ATV-ANA group (P<0.001)
• by 89.8% in the PBO-ANA group (P<0.001)

The HDL-TG content decreased:

• by 53.7% in the ATV-ANA group (P<0.001)
• by 46.6% in the PBO-ANA group (P<0.001)

CETP mass increased because of a significant reduction in the fractional clearance rate of CETP with no change in the CETP production rate:

• by 108% in the ATV-ANA group (P<0.001)
• by 91.2% in the PBO-ANA group (P=0.002)

Conclusion

In this study, treatment with anacetrapib increased the HDL apoA-I and CETP levels by decreasing their fractional clearance rate. This is the first report of the effects of a CETP inhibitor on the metabolism of CETP.

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