Effects of Dalcetrapib in Patients With a Recent Acute Coronary Syndrome
What is the clinical impact of raising high-density lipoprotein (HDL) cholesterol levels by inhibition of cholesteryl ester transfer protein (CETP) using dalcetrapib?
The dal-OUTCOMES trial investigators randomized 15,871 patients with a recent acute coronary syndrome to receive the CETP inhibitor dalcetrapib, at a dose of 600 mg daily, or placebo on a background of optimal medical therapy. The primary efficacy endpoint was a composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation. The median follow-up was 31 months.
At the time of randomization, the mean HDL cholesterol level was 42 mg/dl and the mean low-density lipoprotein (LDL) cholesterol level was 76 mg/dl. Over the course of the trial, HDL cholesterol levels increased from baseline by 4% to 11% in the placebo group, and by 31% to 40% in the dalcetrapib group, with minimal changes in LDL levels. The trial was terminated due to futility at a prespecified interim analysis that included 1,135 primary endpoint events (71% of the projected total number). Compared with placebo, dalcetrapib did not impact the primary endpoint (8.0% vs. 8.3%; hazard ratio with dalcetrapib, 1.04; 95% confidence interval, 0.93-1.16; p = 0.52) or any component of the secondary endpoint or mortality. Patients treated with dalcetrapib had an increase in C-reactive protein level of 0.2 mg/L, and in mean systolic blood pressure of 0.6 mm Hg (p < 0.001 for both comparisons).
The CETP inhibitor dalcetrapib did not reduce the risk of adverse cardiovascular events despite a significant increase in HDL levels.
The strong inverse association between HDL levels and adverse cardiac outcome has prompted many studies to raise HDL, although the clinical impact of such interventions has been limited at best. In patients treated with statins, no study has demonstrated any improvement in mortality or morbidity with such a strategy, and both niacin (AIM-HIGH trial) and CETP inhibitors have failed to impact clinical outcomes. It is quite likely that functionality of HDL may be more important than simply measuring the levels of HDL, and optimization of HDL function may emerge as the next frontier in prevention research.
Keywords: Cholesterol, Acute Coronary Syndrome, Cholesterol Ester Transfer Proteins, Sulfhydryl Compounds, Lipoproteins
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