DEFINE ( Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib) trial

The results of the DEFINE ( Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib) trial were presented at the recent AHA meet. It was a double-blind randomized trial in which patients received either 100 mg of anacetrapib or matching placebo daily. Anacetrapib is an orally active, potent, selective CETP inhibitor that has had an acceptable side-effect profile in initial studies involving healthy volunteers and patients with hyperlipidemia.

The primary efficacy end points were the percentage change from baseline in LDL cholesterol after 24 weeks of treatment and the safety and side-effect assessments (i.e., assessment of adverse events; laboratory testing related to safety, including measurement of electrolyte and aldosterone levels; and assessment of vital signs, including blood-pressure measurement, electrocardiography, and physical examination) throughout the 76-week treatment period. Secondary efficacy end points included the change in LDL cholesterol from baseline to week 76 and the levels of HDL cholesterol, non-HDL cholesterol, apolipoprotein B, and apolipoprotein A-I after 24 and 76 weeks of treatment.

By 24 weeks, LDL cholesterol levels had decreased from 81 mg per deciliter to 45 mg per deciliter (1.2 mmol per liter) in the anacetrapib group, as compared with a change from 82 mg per deciliter (2.1 mmol per liter) to 77 mg per deciliter (2.0 mmol per liter) in the placebo group — a 39.8% reduction with anacetrapib beyond that seen with placebo (P<0.001).

HDL cholesterol levels had increased from 41 mg per deciliter to 101 mg per deciliter (2.6 mmol per liter) in the anacetrapib group, as compared with a change from 40 mg per deciliter (1.0 mmol per liter) to 46 mg per deciliter (1.2 mmol per liter) in the placebo group — a 138.1% increase with anacetrapib beyond that seen with placebo (P<0.001).

In the anacetrapib group, apolipoprotein B levels decreased by 21.0% and apolipoprotein A-I levels increased by 44.7% beyond the changes seen in the placebo group (P<0.001).

 Treatment with anacetrapib was associated with a 31.7% reduction in non-HDL cholesterol, a 36.4% reduction in lipoprotein(a) levels, and a 6.8% reduction in triglyceride levels, beyond the changes seen in the placebo group. All the changes in lipid levels were sustained throughout the 76-week treatment period. There were no significant differences in C-reactive protein levels between the two treatment groups.

Adverse events: There were no appreciable differences between the anacetrapib group and the placebo group in the percentage of patients with adverse events that were thought to be related to the study drug or that led to its discontinuation. There were also no significant differences between the two groups in the mean change in systolic or diastolic blood pressure or in the percentage of patients with a reported increase in blood pressure.

There were no cases of rhabdomyolysis in either study group and no significant differences in the percentages of patients with myalgias or other muscle symptoms or with elevations in creatine kinase.

In the current study, anacetrapib treatment did not alter blood pressure, electrolyte levels, or serum aldosterone levels, and the distribution of cardiovascular events between the two treatment groups provided a 94% predictive probability (confidence) that treatment with anacetrapib is not associated with the rate of adverse cardiovascular effects reported with torcetrapib. These findings have opened the door to retesting the hypothesis that inhibition of CETP is cardioprotective.

http://www.nejm.org/doi/pdf/10.1056/NEJMoa1009744