Therapeutic rationale for CETP inhibition in doubt
MedWire News: Low levels of cholesteryl ester transfer protein (CETP) are associated with an increased risk for death and cardiovascular events in nondiabetic patients with coronary artery disease (CAD), an analysis of clinical trial data suggests.
The findings are in line with data from other recent studies and raise doubts about the value of CETP as a target for therapeutic intervention.
CETP inhibition is currently under study as a potential strategy for preventing CAD but the precise role of CETP in atherogenesis is not fully understood.
To investigate further, Phillip Eller (Innsbruck Medical University, Austria) and team analyzed data from the KAROLA study. This is a prospective, observational study of 1132 patients with CAD and a median follow-up of 8 years.
Median CETP levels at baseline were 1.11 mg/dl, report Eller et al in the European Journal of Clinical Investigation.
CETP levels were lower in men than in women, and lower in patients with low plasma levels of low-density lipoprotein cholesterol or high plasma levels of triglycerides (all differences statistically significant).
In addition, CETP levels were significantly lower in patients taking lipid-lowering drugs and directly correlated with levels of interleukin-6 and adiponectin.
Kaplan-Meier survival analyses found no significant difference in mortality or cardiovascular events between patients in the highest (>1.38 mg/dl) versus lowest (≤0.87 mg/dl) CETP quartiles, after adjusting for age and gender (adjusted hazard ratios [HRs]= 1.26 and 1.22, respectively).
In a post hoc analysis that excluded diabetic individuals, however, patients in the lowest CETP quartile had significantly higher risks for both mortality and cardiovascular events than those in the highest (adjusted HRs=1.46 and 1.28, respectively).
Furthermore, nondiabetic individuals with CETP levels below versus above the median level had an adjusted HR for death of 1.84.
“We performed these post hoc analyses in nondiabetic patients because diabetic patients suffer from an inherent diabetic dyslipidemia, which might obliterate an effect of intrinsic CETP inhibitor,” explain the researchers.
They admit that the association between low CETP and cardiovascular outcomes does not infer a direct causal relationship between the two parameters.
Nevertheless they conclude: “Taken together, our data challenge the pharmacologic principle of CETP inhibition. Increasing HDL-cholesterol levels by pharmacologic CETP inhibition is not effective for preventing CAD, as it seems to be at the expense of decreased HDL function.
“CETP is essential for proper HDL function, and given the accumulating epidemiologic evidence it appears crucial to reassess its role as a target for therapeutic intervention.”
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By Joanna Lyford