Anacetrapib: new hope for cholesteryl ester transfer protein inhibitors in the treatment of dyslipidemia

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Anacetrapib is an investigational cholesteryl ester transfer protein (CETP) inhibitor with indications for the treatment of patients with dyslipidemia.


To establish the pharmacodynamics and lipidaltering efficacy of anacetrapib and its effects on ambulatory blood pressure (ABP).


This paper reported the results of two doubleblind, randomized phase I trials. The pharmacodynamics study enrolled patients aged 18-75 years with dyslipidemia and mixed hypercholesterolemia (lipid levels 100-190 ml/dl). Exclusion criteria were history of cardiac arrhythmias or chronic heart failure, hepatic or hepatobiliary disease, uncontrolled metabolic, endocrine or hematological disease, and disorders of the gastrointestinal or central nervous systems. After a 2-4 week pharmacologic washout period and 2-week dietary run-in, patients were randomly assigned to receive 0 mg/day (placebo), 10 mg/day, 40 mg/day, 150 mg/day, or 300 mg/day anacetrapib with food for 28 days. Serum lipoproteins were measured at baseline, predose, and postdose. The second study was a two-period, crossover trial performed in healthy participants aged 45-75 years with blood pressures (BPs) below 140/90 mmHg. Individuals were not enrolled if they had cardiovascular, metabolic, hepatic, or gall-bladder disease, a history of psychiatric disorders, BMI greater than 40 kg/m2, or estimated creatinine clearance less than 60 ml/min. Eligible participants were randomly assigned to receive 0 mg/day (placebo) or 150 mg/day anacetrapib with a low-calorie, low-fat meal (373 kcal; 20% fat) for 10 days. There was then a 14-day wash-out period before the treatment groups were switched. Measurement of 24 h ABP took place on days one and ten of each treatment period.


For the pharmacodynamic study, the primary outcome measure was change in HDL-cholesterol and LDL-cholesterol levels. For the blood pressure study, the end point was change in 24 h ABP.


The pharmacodynamic study randomized 50 patients, 10 to each dose of anacetrapib and 10 to placebo. After 4 weeks, HDL-cholesterol levels of patients receiving anacetrapib were significantly higher than those of patients on placebo (P = 0.0039 for comparison with 10 mg/day anacetrapib; P <0.0001 for the other three doses). Furthermore, patients receiving 40 mg/day, 150 mg/day, and 300 mg/day anacetrapib also had lower LDL-cholesterol levels at 4 weeks than did those in the placebo group (P <0.0001 for all). At peak efficacy, anacetrapib (300 mg/day) increased HDL cholesterol by 129% and reduced LDL cholesterol by 38% compared with placebo. The BP study (n = 22) did not reveal any significant differences in ABP between patients on anacetrapib and those on placebo (systolic BP 111.82 mmHg vs 111.22 mmHg, least squares mean difference 0.60 mmHg, 95% CI -1.54 to 2.74; P = 0.634). Anacetrapib was not associated with any clinically significant adverse events in either of the trials.


Anacetrapib is associated with significantly increased levels of HDL cholesterol and decreased LDL cholesterol in patients with dyslipidemia, and does not appear to affect BP.

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