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Background— Torcetrapib, an inhibitor of cholesteryl ester transfer protein, has been shown to increase the cardiovascular event rate despite conferring a significant high-density lipoprotein cholesterol increase. Using data from the Rating Atherosclerotic Disease Change by Imaging with a New CETP Inhibitor (RADIANCE) trials, which assessed the impact of torcetrapib on carotid intima-media thickness (cIMT), we sought to explore potential mechanisms underlying this adverse outcome. Methods and Results— Data from the RADIANCE 1 and 2 studies, which examined cIMT in 904 subjects with familial hypercholesterolemia and in 752 subjects with mixed dyslipidemia, were pooled. Subjects were randomized to either atorvastatin or torcetrapib combined with atorvastatin. Mean common cIMT progression was increased in subjects receiving torcetrapib plus atorvastatin compared with subjects receiving atorvastatin alone (0.0076±0.0011 versus 0.0025±0.0011 mm/y; P =0.0014). Subjects treated with torcetrapib plus atorvastatin displayed higher postrandomization systolic blood pressure and plasma sodium and bicarbonate levels in conjunction with lower potassium levels. The decrease in potassium levels was associated with the blood pressure increase. Markedly, the use of renin-angiotensin-aldosterone system inhibitors tended to aggravate the blood pressure increase. Subjects receiving torcetrapib plus atorvastatin with the strongest low-density lipoprotein cholesterol reduction showed the smallest cIMT progression, whereas subjects with the highest systolic blood pressure increase showed the largest cIMT progression. High-density lipoprotein cholesterol increase was not associated with cIMT change. Conclusions— These analyses support mineralocorticoid-mediated off-target toxicity in patients receiving torcetrapib as a contributing factor to an adverse outcome. The absence of an inverse relationship between high-density lipoprotein cholesterol change and cIMT progression suggests that torcetrapib-induced high-density lipoprotein cholesterol increase does not mediate atheroprotection. Future studies with cholesteryl ester transfer protein inhibitors without off-target toxicity are needed to settle this issue.

Background — Cholesteryl ester transfer protein (CETP) mediates the transfer of neutral lipids between lipoproteins. High plasma levels of CETP are correlated with low HDL cholesterol levels, a strong risk factor for coronary artery disease. In earlier studies, JTT-705, a novel CETP inhibitor, was shown to increase plasma HDL cholesterol and to inhibit the progression of atherosclerosis in cholesterol-fed rabbits. This study describes the first results using this CETP inhibitor in humans. Methods and Results — In a randomized, double-blind, and placebo-controlled trial, we evaluated the efficacy and safety of daily treatment with 300, 600, and 900 mg JTT-705 in 198 healthy subjects with mild hyperlipidemia. Treatment with 900 mg JTT-705 for 4 weeks led to a 37% decrease in CETP activity ( P P P =0.017), whereas levels of triglycerides, phospholipid transfer protein, and lecithin-cholesterol acyltransferase were unaffected. In line with the increase of total HDL, a rise of HDL 2, HDL 3 , and apolipoprotein A-I was also noted. JTT-705 showed no toxicity with regard to physical examination and routine laboratory tests. Conclusions — We show that the use of the CETP inhibitor JTT-705 in humans is an effective means to raise HDL cholesterol levels with minor gastrointestinal side effects ( P =0.06). Although these results hold promise, further studies are needed to investigate whether the observed increase in HDL cholesterol translates into a concomitant reduction in coronary artery disease risk.

predominantly associated with Lp(a), 2 the increased OxPL/apoB ratio could be explained by the shift in the Lp(a)/LDL ratio. Similarly, in the placebo-treated group the decreased OxPL/apoB ratio results from a decrease in Lp(a) relative to LDL. It is therefore unlikely that the OxPL/apoB ratio is a surrogate marker of net removal of OxPL from the vessel wall. Moreover, the observed 30% decrease in total plasma apoB-OxPL also argues against an increased net efflux of OxPL from the vessel wall. Recently, using the OxLDL assay from Mercodia in which an oxidation epitope associated with apoB is detected with monoclonal antibody 4E6, we found that atorvastatin (80 mg/d) and simvastatin (40 mg/d) reduced total plasma Ox-apoB (43% and 35%, respectively) in patients with familial hypercholesterolemia from the ASAP study.3 Interestingly, we observed no change in the Ox-apoB/apoB ratio when we used the noncompetitive version of the kit, in which the immobilized antibody captures Ox-apoB from the sample. We did, however, observe a small increase in the Ox-apoB/apoB ratio (18% for atorvastatin, 13% for simvastatin) when we used the competitive version, which unlike the noncompetitive version is sensitive to the number of oxidation epitopes associated with apoB. In addition, the increase in Ox-apoB/apoB ratio can be explained by an increase in Lp(a) relative to LDL. To further address this question, measurements of OxLDL with E06 and 4E6 in welldesigned assays (eg, in isolated Lp(a) particles) at different time points after the start of statin treatment are required.

Background— Familial combined hyperlipidemia (FCH) is traditionally diagnosed by total plasma cholesterol and/or triglyceride levels above the 90th percentile adjusted for age and gender. In a recent study, we showed that the diagnosis of FCH on the basis of these diagnostic criteria was inconsistent in 26% of the subjects over a 5-year period. This result emphasizes the need for reevaluation of the diagnostic criteria for FCH. Methods and Results— A total of 32 families (299 subjects) were studied in 1994 and 1999. A subject was defined “truly” FCH when diagnosed FCH in 1994 and/or 1999 on the basis of traditional plasma lipid criteria. Additional lipid and lipoprotein parameters, including apolipoprotein B (apoB) and small, dense LDL, were measured at both time points. In total, 121 subjects (40%) were defined as truly FCH. Multivariate analysis revealed that absolute apoB values combined with triglyceride and total cholesterol levels adjusted for age and gender best predicted truly FCH. A nomogram including these parameters is provided to simply and accurately calculate the probability to be affected by FCH. Furthermore, it is shown that when percentiles of triglyceride and total cholesterol adjusted for age and gender are not available in a population, the definition of FCH can be established on the basis of hypertriglyceridemia (>1.5 mmol/L) and hyper-apoB (>1200 mg/L). Conclusions— The diagnosis of FCH is best predicted by absolute apoB levels combined with triglyceride and total cholesterol levels adjusted for age and gender and can accurately be calculated by a nomogram. This definition is also a good predictor of cardiovascular risk in FCH.