CETP inhibitor anacetrapib induces beneficial changes in lipid profile
MedWire News: Individuals at risk for developing coronary heart disease (CHD) may benefit from treatment with anacetrapib, a selective cholesteryl ester transfer protein (CETP) inhibitor, suggest study findings that show beneficial changes in lipid profile.
These results provide a potential alternative treatment for increasing high-density lipoprotein (HDL) cholesterol among high-risk patients, such as those with CHD or diabetes, where a high residual risk for cardiovascular events remains despite intensive low-density lipoprotein cholesterol lowering with statins, write the authors.
Enhanced CETP activity may be proatherogenic and thus inhibition of its activity may prove to be atheroprotective. To investigate, Ronald Krauss (Children's Hospital Oakland Research Institute, California, USA) and colleagues randomly allocated 30 healthy individuals to once-daily oral treatment for 14 consecutive days with anacetrapib 20 mg, anacetrapib 150 mg, or placebo.
Blood samples for lipid and lipoprotein analyses were collected before the first dose on day 1 and 24 hours post-dose on the last day of treatment.
Whole plasma lipid and lipoprotein analyses showed that by the end of treatment, anacetrapib 150 mg/day had resulted in significant placebo-adjusted decreases in LDL cholesterol (26%; 119 to 83 mg/dL) and apolipoprotein (apo)B (29%; 79 to 57 mg/dL) from baseline levels. In addition, significant increases in HDL cholesterol (82%; 42 to 78 mg/dL) and apoA1 (21%; 118 to 143 mg/dL) were seen at this dose.
Treatment with anacetrapib 150 mg/day also resulted in significant placebo-adjusted reductions in mean particle concentrations of medium very-low-density lipoprotein (VLDL), small VLDL, large intermediate-density lipoprotein (IDL), medium LDL2a and 2b, and small LDL3a. A significant increase was also seen for very small LDL4b.
In addition, the team found a significant increase in triglycerides and reductions of cholesteryl esters (CE) in VLDL, IDL, and the densest LDL fraction. Levels of large buoyant HDL particles were significantly increased and enrichment of CE, apoAI, and apoCIII was also observed in the mid-HDL density range.
Overall, changes in lipoprotein subfraction concentrations and composition with anacetrapib 20 mg/day were similar to those for the 150 mg/day dose, but were generally smaller in effect.
Writing in the Journal of Lipid Research the researchers conclude: "While the dramatic increases in HDL cholesterol and reductions in LDL cholesterol induced by anacetrapib as well as other CETP inhibitors suggest a potentially significant benefit on cardiovascular disease risk, it is not yet known whether the metabolic bases for these effects… might alter their physiological and pathological functions.
"Ultimately, determination of the efficacy of anacetrapib for reducing major coronary events awaits the completion of REVEAL, a clinical outcomes trial in 30,000 patients with cardiovascular disease at high risk for major coronary events."
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By Ingrid Grasmo