Despite the success of statins for both primary and secondary prevention, many patients continue to have a high residual risk of cardiovascular events related to sub-optimal lipid control. One approach to raising HDL cholesterol is to inhibit the cholesteryl ester transfer protein (CETP), a plasma protein that promotes the transfer of cholesteryl esters from HDL and other lipoprotein fractions, with inhibition of CETP increasing HDL, and concomitantly lowering LDL. The first CETP inhibitor to make it to Phase III trial was torcetrapib in the ILLUMINATE study, but this was terminated early after the drug was shown to paradoxically cause an excess of deaths and cardiovascular events. Analysis of these results suggested that torcetrapib was acting off-target and increasing blood pressure, and that the adverse effects were not related to CETP inhibition per se. While torcetrapib was hastily jettisoned, development on other CETP inhibitors has continued and in this large study the safety of anacetrapib was assessed.
In a randomized, double-blind, placebo-controlled trial in patients with coronary heart disease or at high risk for coronary heart disease who were taking a statin, 1623 individuals were assigned to receive 100 mg of anacetrapib or placebo daily for 18 months. The primary end points were the percent change from baseline in LDL cholesterol at 24 weeks (HDL cholesterol level was a secondary end point) and the safety and side-effect profile of anacetrapib through 76 weeks. Cardiovascular events and deaths were prospectively adjudicated. By 24 weeks, the LDL cholesterol level had been reduced from 2.1 mmol/l to 1.2 mmol/l in the anacetrapib group, as compared with a reduction from 2.1 mmol/l to 2.0 mmol/l in the placebo group (a 39.8% reduction with anacetrapib, P<0.001). In addition, the HDL cholesterol level increased from 1.0 mmol/l to 2.6 mmol/l in the anacetrapib group, as compared with an increase from 1.0 mmol/l to 1.2 mmol/l in the placebo group (a 138.1% increase with anacetrapib, P<0.001). Through 76 weeks, no changes were noted in blood pressure or electrolyte or aldosterone levels with anacetrapib as compared with placebo. Prespecified adjudicated cardiovascular events occurred in 16 patients treated with anacetrapib (2.0%) and 21 patients receiving placebo (2.6%) (P = 0.40). The prespecified Bayesian analysis indicated that this event distribution provided a predictive probability of 94% that anacetrapib would not be associated with a 25% increase in cardiovascular events, as seen with torcetrapib.
Treatment with anacetrapib had robust effects on LDL and HDL cholesterol, had an acceptable side-effect profile, and, within the limits of power of this study, did not result in the adverse cardiovascular effects observed with torcetrapib. Larger studies will be needed to assess its efficacy on relevant clinical outcomes.
- Cannon CP, Shah S, Dansky HM et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010 Dec 16;363(25):2406-15.