CETP and mortality: Expert Analysis
Data from the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study suggest that low CETP levels are associated with increased mortality, contrary to extensive published evidence (1,2). Professor Philip Barter, HDL Forum Editor, Heart Research Institute, Sydney Australia provides expert analysis of the study here.
Ritsch A, Scharnagl H, Eller P et al. Cholesteryl ester transfer protein and mortality in patients undergoing coronary angiography. The Ludwigshafen Risk and Cardiovascular Health Study. Circulation 2010;121:366-74.
LURIC is a prospective, observational study of patients at intermediate to high cardiovascular risk. A cohort of 3,256 participants (63% with CAD) referred for baseline coronary angiography between 1997-2000 and with fasting blood samples (lipids, CETP and inflammatory markers) were included in this analysis. Primary endpoints were cardiovascular and all-cause mortality.
At baseline, all cardiovascular risk factors were more prevalent in patients with than in those without CAD. Patients with CAD had lower plasma levels of HDL cholesterol (29 mg/dL vs. 33 mg/dL, p<0.001) and CETP than those without CAD (1.07 mg/dL versus 1.16 mg/dL, p=0.002). There was a modest inverse association between the HDL cholesterol levels and CETP levels (p=0.027). Plasma CETP was also negatively correlated with inflammatory markers, such as high-sensitivity C-reactive protein and interleukin-6.
After a median follow-up of 7.75 years, there were 754 deaths, 474 (63%) due to cardiovascular disease. After adjusting for pre-existing CAD, the use of lipid-lowering drugs, the presence of diabetes and conventional cardiovascular risk factors, patients with CETP plasma levels in the lowest quartile (<0.91 mg/dL) had 33% increased risk for all-cause death (95% CI 7-65%, p=0.011), as well as 37% increased risk for cardiovascular death (95% CI 3-81%, p=0.029) compared with those in the highest quartile (>1.56 mg/dL) (Table 1). The prognostic value of CETP was also evident in the subgroup with angiographic evidence of CAD.
The authors concluded that low endogenous plasma CETP levels were associated with increased cardiovascular and all-cause mortality in this moderate to high risk patient population.
Expert analysis
‘This report by Andreas Ritsch and colleagues challenges the rationale that pharmacological inhibition of CETP has the potential to be anti-atherogenic. This is despite extensive evidence to the contrary from animal and human studies, reviewed in detail in the CETP Inhibition Position Paper (3),’ commented Professor Barter.
The findings of this study do need be taken in the context of its design. This report details post hoc analyses based on single plasma CETP measurements taken at baseline (on referral for coronary angiography) in a cohort of patients with and without CAD in this observational study. The association between plasma levels of HDL cholesterol and CETP was relatively modest, which may be reflective of the range of triglyceride levels in the patient population (median levels 131 mg/dL without CAD and 148 mg/dL with CAD). Finally, as the cohort was of moderate to high cardiovascular risk, the results of the analysis cannot be extrapolated to the general population.
The authors do raise a valid point in highlighting the importance of HDL functionality when considering the role of CETP in atherogenesis. Thus, not only do we need to take account of HDL cholesterol levels but also the functionality of the HDL particles. Raising HDL cholesterol levels may be insufficient if this comes at the cost of reduced HDL functionality, and in turn reduced capacity for reverse cholesterol transport.
Clearly controversy surrounding the potential therapeutic role of CETP inhibition will continue until the results of ongoing outcomes studies with dalcetrapib and anacetrapib are available.
References
1. Marschang P, Sandhofer A, Ritsch A et al. Plasma cholesteryl estr transfer protein concentrations predict cardiovascular events in patients with coronary artery disease treated with pravastatin. J Intern Med 2006;260:151-9.
2. Boekholdt SM, Kuivenhoven JA, Wareham NJ et al. Plasma levels of cholesteryl ester transfer protein and the risk of future coronary artery disease in apparently healthy men and women: the Prospective EPIC (European Prospective Investigation into Cancer and nutrition)-Norfolk Population Study. Circulation 2004;110:1418-23
3. CETP Inhibition Position Statement. Available at http://www.cetpiforum.org/250608position.html.
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