The inhibition of cholesteryl ester transfer protein (CETP) is considered a potential new mechanism for treatment of dyslipidaemia. Anacetrapib (MK-0859) is a CETP inhibitor currently under development. We aimed to assess anacetrapib's effects as monotherapy on low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) and on 24-h ambulatory blood pressure.

We did two double-blind, randomised, placebo-controlled phase I studies. In the first study, 50 patients with dyslipidaemia (LDL-C 100–190 mg/dL; 40 active, 10 placebo) aged 18–75 years received anacetrapib doses of 0, 10, 40, 150, or 300 mg orally once a day with a meal for 28 days. Standard lipid and lipoprotein monitoring, safety monitoring, and anacetrapib concentrations for pharmacokinetics were done. In the second study, 22 healthy participants aged 45–75 years received either 150 mg of anacetrapib once a day or matching placebo with a meal for 10 days in each crossover period, in a randomised sequence, with at least a 14-day washout between the treatment periods. Continuous 24-h ambulatory blood pressure monitoring was done on day −1 and day 10 of each treatment period in this study. The primary or secondary endpoints of safety and tolerability were assessed in both studies by monitoring clinical adverse experiences, physical examinations, vital signs, 12-lead electrocardiogram, and laboratory safety. Analysis was per protocol. These trials are registered with ClinicalTrials.gov, number NCT00565292 and NCT00565006.

In the dyslipidaemia study, one patient withdrew consent and one was excluded from the data analysis for HDL-C and LDL-C because complete pre-dose measurements were not available. Anacetrapib produced dose-dependent lipid-altering effects with peak lipid-altering effects of 129% (mean 51·1 [SD 3·8]−114·9 [7·9] mg/dL) increase in HDL-C and a 38% (138·2 [11·4]−77·6 [7·9] mg/dL) decrease in LDL-C in patients with dyslipidaemia. In the 24-h ambulatory blood pressure study in healthy individuals, least squares difference between anacetrapib and placebo groups on day 10 were 0·60 (90% CI −1·54 to 2·74; p=0·634) mm Hg for systolic blood pressure and 0·47 (90% CI −0·90 to 1·84; p=0·561) mm Hg for diastolic blood pressure.

Anacetrapib seems to exhibit HDL-C increases greater than those seen with other investigational drugs in this class and LDL-C lowering effects similar to statins. Despite greater lipid-altering effects relative to other members of this class, anacetrapib seems not to increase blood pressure, suggesting that potent CETP inhibition by itself might not lead to increased blood pressure.