dalcetrapib and Hyperlipoproteinemia-Type-II

Cholesteryl ester transfer protein (CETP) inhibitors are currently being investigated because of their ability to increase high-density lipoprotein cholesterol levels. In various metabolic settings, the relationship between CETP and lipoprotein metabolism is complex and may depend largely on the concentration of triglyceride-rich lipoproteins. Two CETP inhibitors, JTT-705 and torcetrapib, are in an advanced phase of development. Following hopeful intermediate results, a large endpoint study using torcetrapib has just been discontinued due to increased mortality in torcetrapib-treated subjects. In this review we summarize clinical data on the use of CETP inhibitors.

Topics: Amides; Anticholesteremic Agents; Cholesterol Ester Transfer Proteins; Clinical Trials as Topic; Dyslipidemias; Esters; Female; Humans; Hyperlipoproteinemia Type II; Hypertriglyceridemia; Male; Quinolines; Sulfhydryl Compounds

While elevated plasma HDL levels are inversely correlated with cardiovascular events, raising HDL with the CETP inhibitor torcetrapib, however, was associated with increased cardiovascular morbidity and mortality in the ILLUMINATE trial. Whether the deleterious clinical effects of torcetrapib represent a molecule specific off-target effect, a class effect of CETP inhibitors or both is matter of ongoing debate. As such, the aim of the present study was to investigate whether CETP-inhibition with JTT-705, a molecule distinctly different from torcetrapib, impacts on vascular function, a well-established surrogate of atherosclerotic vascular disease, as well as markers of inflammation and oxidative stress in patients with type II hyperlipidemia.. Eighteen patients were randomized to receive JTT-705 600 mg/d or matching placebo for 4 weeks. Flow-mediated dilation (FMD) was measured using ultrasonography of the brachial artery. HDL-C increased by 26% from 1.14 mmol/l to 1.44 mmol/l (p=0.01) in the JTT-705 group, while triglycerides decreased from 2.52 mmol/l to 1.97 mmol/l (p=0.03). CETP- inhibition with JTT-705, however, did not change FMD (3.1+/-0.6% to 3.6+/-0.4%; p=0.48). Interestingly, in a sub group analysis of patients with lower than median HDL-C (<1.19 mmol/l), FMD increased by 41% in patients vs. patients with higher than median HDL-C (>1.19 mmol/l; p=0.01). Markers of vascular inflammation (CRP, ICAM-1, IL-6, TNF alpha), as well as plasma endothelin-1 levels all remained unchanged throughout the study.. In patients with type II hyperlipidemia, CETP inhibition with JTT-705 increased HDL-C and lowered triglycerides but improved endothelial function in the subgroup of patients with low baseline HDL-C levels only.

Topics: Amides; Anticholesteremic Agents; Blood Pressure; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Double-Blind Method; Endothelium, Vascular; Esters; Female; Humans; Hyperlipoproteinemia Type II; Male; Middle Aged; Sulfhydryl Compounds; Triglycerides