Anacetrapib and Cholesterol for Patients with Coronary Heart Disease

Anacetrapib has been shown to lower low-density lipoprotein cholesterol (LDL-C) and significantly increase high-density lipoprotein cholesterol (HDL-C) in patients with or at risk for coronary heart disease while maintaining an acceptable side effect profile, according to one recent safety study. The results of the DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib) trial were recently published online in the New England Journal of Medicine [2010; 10.1056/NEJMoa1009744]. High levels of LDL-C and low levels of HDL-C can be major risk factors for the development of cardiovascular disease. Cholesteryl ester transfer protein (CETP) inhibitors have been shown to increase HDLC and reduce LDL-C; however, in previous clinical studies, torcetrapib—the first CEPT inhibitor tested—was found to have significant safety concerns. In this study, researchers created a randomized, double-blind study to assess the safety and efficacy of anacetrapib, another CETP inhibitor, for patients with or at high risk for coronary heart disease. Participants in the study were between the ages of 18 and 80 years, had an LDL-C level between 50 and 100 mg/dL while taking a statin with or without other lipid-modifying drugs, had an HDL-C level that was <60 mg/dL, and had a triglyceride level of 400 mg/dL. To be included, participants from 153 centers in 20 countries also needed to have either prior known coronary heart disease or a Framingham risk score of >20% per 10 years for developing the disease. Those in the study (n=1623) were randomly assigned to either receive 100 mg of anacetrapib or a matching placebo daily for 18 months. All patients were also encouraged to eat a cholesterol-lowering diet and continue taking lipid-modifying therapies during the study period. Researchers identified the primary end points of the study as the percentage change from baseline in LDL-C after 24 weeks of treatment and the safety and side effect profile for the entire 76 weeks of treatment. Secondary end points included the change in LDL-C from the baseline to week 76 and the levels of HDL-C and non–HDL-C at weeks 24 and 76. Researchers found that at the 24-week mark, the LDL-C levels had decreased from 81 to 45 mg/dL in the anacetrapib group. In the placebo group, the decrease in LDL-C levels was smaller (from 82 to 77 mg/dL). The reduction in the anacetrapib group was 39.8% greater than in the placebo group (P<.001). Patients receiving anacetrapib had an increase of HDL-C levels that was 138.1% (P<.001) greater than the placebo group. Based on the results, the anacetrapib group increased HDL-C levels from 41 to 101 mg/dL, while the placebo group increased from 40 to 46 mg/dL. Those patients in the anacetrapib group also saw a 31.7% greater reduction in non–HDL-C levels, a 36.4% greater reduction in lipoprotein(a) levels, and a 6.8% greater reduction in triglyceride levels when compared with the placebo group. The study’s authors reported that the anacetrapib group had an acceptable side effect profile throughout the 76 weeks of treatment. There was no significant difference between the 2 groups in terms of blood pressure changes or changes to serum levels of potassium, chloride, bicarbonate, or aldosterone. In addition, researchers found that the adjudicated composite of cardiovascular end point—which included death from cardiovascular causes, myocardial infarction, hospitalization for unstable angina, or stroke—occurred in 2.0% of patients in the anacetrapib group and 2.6% of patients in the placebo group (P=.40). They also used a Bayesian analysis to determine that with 94% predictive probability, the 25% increase in cardiovascular events seen with torcetrapib would not be seen with anacetrapib. However, according to the authors, there were several limitations to their study and further trials may be needed to verify the drug’s safety. The limitations included a small study size, mostly white study participants, and no long-term safety information about reducing LDL-C levels to such low levels.