Anacetrapib
First-in-class phase I trials show anacetrapib raises HDL-C by 129% and lowers LDL-C by 38% without raising blood pressure (Lancet 2007)
Original title: Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies
Two double-blind, randomised, placebo-controlled phase I studies assessed anacetrapib as monotherapy (NCT00565292, NCT00565006). In the first, 50 dyslipidaemic patients (LDL-C 100-190 mg/dL; 40 active, 10 placebo) received anacetrapib 0, 10, 40, 150, or 300 mg daily for 28 days. Anacetrapib produced dose-dependent lipid effects, peaking at a 129% increase in HDL-C (51.1 to 114.9 mg/dL) and a 38% decrease in LDL-C (138.2 to 77.6 mg/dL). In the second study, 22 healthy participants aged 45-75 received anacetrapib 150 mg or placebo for 10 days per crossover period with 24-hour ambulatory blood pressure monitoring; the least-squares difference from placebo on day 10 was 0.60 mm Hg systolic (90% CI -1.54 to 2.74, p=0.634) and 0.47 mm Hg diastolic (90% CI -0.90 to 1.84, p=0.561), showing no meaningful blood pressure effect. These first published human data established that the HDL-raising and LDL-lowering effects of anacetrapib exceed those of other CETP inhibitors while, unlike torcetrapib, it does not raise blood pressure, suggesting potent CETP inhibition alone need not cause hypertension.
Original abstract
Background: 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.
Methods: 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.
Findings: 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.
Interpretation: 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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.