See Articles page 1907 In today’s Lancet, Rajesh Krishna and colleagues report two doubled-blind, placebo-controlled, randomised phase I studies with the cholesteryl ester transfer protein (CETP) inhibitor, anacetrapib, in healthy individuals and in patients with dyslipidaemia. 1 The drug increased HDL cholesterol and decreased LDL cholesterol. Importantly, there was no effect on blood pressure. LDL and HDL are independent factors that modulate the risk of cardiovascular disease, and increases in HDL cholesterol might decrease cardiovascular risk. 2 CETP inhibitors raise HDL and decrease LDL. Torcetrapib was the first tested in large long-term trials (ILLUMINATE, 3 RADIANCE I, 4 RADIANCE II, 5 and ILLUSTRATE6). On

Dec 2, 2006, all torcetrapib clinical trials were stopped in the interests of patients’ safety. The data and safety monitoring board on ILLUMINATE recommended termin ation of the study because there were significantly more major cardiovascular events in the group receiving torcetrapib in combination with atorvastatin than in the group receiving atorvastatin monotherapy. 3 In the other trials, torcetrapib failed to reduce the development of atherosclerosis in the common carotid4, 5 and coronary arteries, 6 but increased blood pressure in every study. Torcetrapib induced significant increases in systolic blood pressure (5· 4 mm Hg) and in serum concentra tions of sodium, bicarbonate, and aldosterone, and a significant decrease in serum potassium. 3 Increased risk of death was higher when the increase in bicarbonate or decrease in potas sium was greater than the median change. 8 This off-target effect might have been associated with the increased mortality and morbidity in ILLUMINATE, although further analyses are needed to interpret this relation. Further long-term studies in larger populations will be necessary to confirm the absence of an off-target effect on blood pressure with anacetrapib. This prudence is necessary because torcetrapib and anacetrapib are in the same structural class, and because the effect of torcetrapib on systolic blood pressure was found in large long-term studies; 3–6 the effect was lower7 and even not statistically significant8 in phase 2 studies. Furthermore, in ILLUMINATE, 3 the standard deviations of log-rank tests for the effects of torcetrapib on systolic blood pressure