Torcetrapib blood pressure, increased

Anacetrapib is one of the three currently investigated cholesteryl ester transfer proteins (CETP) (torcetrapib having been discontinued because of serious adverse reactions). This new class of lipid-modifying drugs has substantial capacity to increase high-density lipoprotein (HDL) cholesterol, and anacetrapib was highly efficacious in a multicenter study in 1623 patients with dys-lipidemias, who took 100 mg/day for 76 weeks [l ]. Compared with placebo, anacetrapib did not raise blood pressure or aldosterone concentrations, which are believed to have been responsible for the cardiovascular deaths associated with torcetrapib. 

Cardiovascular As was reported in SEDA-32 (p. 817), ILLUMINATE, an outcome study that recruited around 15 000 statin-eligible patients with coronary heart disease or type 2 diabetes mellitus was terminated after a median follow-up of only 550 days, because of a small but significant increase in major cardiovascular events in those taking torcetrapib - - atorvastatin compared with those taking atorvastatin alone (49 versus 35 cardiovascular deaths) [69. This occurred despite a 72% increase in HDL cholesterol and a 25% reduction in LDL cholesterol compared with the statin alone. This was almost certainly correctly attributed to activation of the renin-angiotensin-aldosterone system, resulting in increments in blood pressure and aldosterone and reduced potassium. 

This experience is worth revisiting. Does it suggest that such large effects on HDL cholesterol cannot overcome the adverse effects of a modest increase in blood pressure Does that itself cast some doubt on the HDL hypothesis, or will other inhibitors of cholesterol ester transfer protein (CETP) reveal problems not associated with blood pressure Several major companies are advanced in their trials of CETP inhibitors. One, anacetrapib, has been found to be free of the mineralocorticoid-related blood pressure effects and is equi-potent with torcetrapib and another compound already in a large outcome trial. These inhibitors bind CETP to HDL and there are differences between the compounds to the extent of the reversibility of the binding [SEDA-32, 816]. 

Inhibition of cholesteryl ester transfer protein (CETP), which mediates the transfer of cholesteryl esters from HDL particles and other lipoprotein fractions to atherogenic apo B-containing lipoproteins, leads to a substantial increase in HDL-Cconcentrations and also reduces LDL-C concentrations. Torcetrapib, the first CETP inhibitor evaluated in phase III clinical trials, caused increases in all-cause mortality and cardiovascular events, despite a dramatic increase in HDL-C concentrations. This paradox was explained by stimulation of aldosterone production, leading to increased blood pressure and low serum potassium [23]. Consequently, the large clinical outcomes trial, ILLUMINATE, was prematurely terminated in 2006. 

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