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The Effect of Cholesteryl Ester Transfer Protein Inhibition on Lipids, Lipoproteins, and Markers of HDL Function After an Acute Coronary Syndrome: The dal-ACUTE Randomized Trial
Study Questions:
Does cholesteryl ester transfer protein (CETP) inhibition influence lipids, inflammation, and markers of high-density lipoprotein (HDL) function after acute coronary syndrome (ACS)?
Methods:
The dal-ACUTE study was a phase 3, double-blind randomized, placebo-controlled trial, which included 31 centers from the Czech Republic, Netherlands, United Kingdom, and United States; conducted from March 2011 to March 2012. The study population included adults ages 45 years or older, hospitalized for ACS, who were clinically stable and less than 1 week out from their event. Participants were randomized in a 1:1 ratio to dalcetrapib 600 mg/day or placebo for 20 weeks. Patients returned for study visits at 4, 8, 12, and 20 weeks. The primary endpoint was percent change in HDL cholesterol (HDL-C) after 4 weeks. Secondary endpoints included apolipoprotein levels, markers of HDL function, and inflammation.
Results:
A total of 300 patients were randomized; two patients randomized to dalcetrapib did not receive the study drug and were excluded from the analysis. Dalcetrapib treatment increased HDL-C and apolipoprotein A1 by 33.7% and 11.8%, respectively (both p < 0.001) and total cholesterol efflux by 9.5% (p = 0.003) after 4 weeks, principally via an increase in non-ATP-binding cassette transporter (ABC) A1-mediated efflux, without statistically significant changes in pre-beta1-HDL levels. The increase in total efflux with dalcetrapib correlated most strongly with increases in apolipoprotein A1 and HDL-C (r = 0.46 and 0.43, respectively) rather than the increase in pre-beta1-HDL (r = 0.32). Baseline and on-treatment ABCA1-mediated efflux correlated most strongly with pre-beta1-HDL levels. In contrast, non-ABCA1-mediated efflux correlated better with apolipoprotein A1 and HDL-C levels. High-sensitivity C-reactive protein levels declined over time, but did not differ from placebo.
Conclusions:
The investigators concluded that HDL raised through CETP inhibition with dalcetrapib improves cholesterol efflux, principally via a non-ABCA1-mediated pathway. While HDL-C was increased by one-third, apolipoprotein A1 and total efflux were increased only by one-tenth, supporting the concept of dissociation between improvements in HDL function and HDL-C levels, which may be of relevance to ongoing trials and the development of therapeutic interventions targeting HDL.
Perspective:
Given that the dal-OUTCOMES trial observed no reduction in cardiovascular events among patients with a recent ACS event randomized to dalcetrapib, function of HDL particles may be more important than total HDL. The data presented in dal-ACUTE suggest that an increase in cholesterol efflux is primarily through non-ABCA1-mediated pathways; however, no change in markers of inflammation or LDL-C and apolipoprotein B levels supports the lack of benefit in the ACS population. Continued research related to HDL function and cholesterol efflux is warranted.
Keywords: Inflammation, United Kingdom, Acute Coronary Syndrome, Czech Republic, High-Density Lipoproteins, Pre-beta, Sulfhydryl Compounds, Lipoproteins, Cholesterol, Dyslipidemias, Cholesterol Ester Transfer Proteins, C-Reactive Protein, Biomarkers, ATP-Binding Cassette Transporters, Netherlands, United States
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