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11-10-2011 | Cardiometabolic | Article

Anacetrapib benefits persist after treatment cessation


Free abstract

MedWire News: Researchers report persistent reductions in low-density lipoprotein (LDL) cholesterol and apolipoprotein (apo)B and increases in high-density lipoprotein (HDL) cholesterol and apoA-I 8 weeks after patients stop treatment with anacetrapib.

"Anacetrapib is an orally active, potent, and selective cholesteryl ester transfer protein (CETP) inhibitor currently in phase III development," write Hayes Dansky (Merck, Sharp & Dohme Corp, Whitehouse Station, New Jersey, USA) and co-authors in the American Heart Journal.

In a previous study, the team showed that 8 weeks of treatment with anacetrapib resulted in decreases in LDL cholesterol and apoB of approximately 40% and 30%, respectively, and increases in HDL cholesterol and apoA-I of approximately 139% and 47%.

In the present study, the researchers report the changes in lipid levels observed during an 8-week follow-up period after discontinuation of anacetrapib treatment.

During the treatment phase, a total of 589 patients with primary hypercholesterolemia or mixed hyperlipidemia were randomly assigned to take daily placebo, atorvastatin 20 mg, or varying doses of anacetrapib (provided as monotherapy or co-administered with atorvastatin 20 mg) for 8 weeks. This was followed by an 8-week follow-up period, during which anacetrapib users were switched to placebo.

At week 16, Dansky and co-authors observed significant mean reductions from baseline in LDL cholesterol of 9.3% and 15.3% for patients treated with anacetrapib 150 and 300 mg, respectively. Increases in HDL cholesterol were also observed, with levels significantly increasing by a mean of 18.6%, 40.5%, and 43.4% for patients receiving anacetrapib 40, 150, and 300 mg, respectively.

The effects on apoB and apoA-I were consistent with the changes observed for LDL and HDL cholesterol, respectively, note the researchers.

They add that the lipid changes persisted in the atorvastatin co-administration groups, but not in the atorvastatin only group.

When plasma anacetrapib concentrations were measured at follow-up, the team found that levels were 18-26% of the values observed during the treatment phase. "The persistence of anacetrapib blood levels in the current study suggests that the drug has a terminal half-life of approximately 3 to 4 weeks," say Dansky et al. They suggest that this may account for the alterations in plasma lipids 8 weeks after cessation of anacetrapib treatment.

The team concludes: "Additional preclinical and clinical studies are being conducted to better understand the pharmacokinetic and pharmacodynamic profile of anacetrapib, its tissue distribution, and the mechanism for the long terminal half-life."

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By Nikki Withers