Is there a future for CETP-inhibitor therapy?

Despite large improvements in cardiovascular disease mortality, coronary heart disease (CHD) and stroke remain the leading causes of death in most nations around the world [1,101]. Statins are the foundation for cardiovascular prevention, with up to 50% reductions in cardiovascular risk with the more potent statins [2]. In both statin-treated and -untreated patients, low levels of high-density lipoprotein cholesterol (HDL-C) are an important predictor of subsequent cardiovascular risk [3,4]. In epidemiologic studies, each 1 mg/dl (0.03 mmol, or ~2–3%, depending on baseline HDL-C level) increase in HDL-C is associated with a 2–4% reduction in the risk of CHD events, independent of low-density lipoprotein cholesterol (LDL-C) levels [5]. Of the drugs currently on the market, niacin is the most effective at raising HDL-C (~25% at the 2-g dose), while statins and fibrates have more modest HDL-C-raising effects (3–10%) [6]. However, it is not clear that pharmacologically raising HDL-C per se with these agents reduces cardiovascular risk. A meta-ana lysis of HDL-C-raising drugs found that after adjusting for LDL-C-lowering, raising HDL-C (or lowering triglycerides) was not associated with further cardiovascular risk reduction [6]. Several classes of HDL-C-raising agents with novel mechanisms of action are under development [7]. Farthest along are the cholesteryl ester transfer protein (CETP) inhibitors. CETP mediates the transfer of cholesteryl esters from HDL to proatherogenic apolipoprotein B-lipoproteins for transportation of cholesterol back to the cells; blocking CETP increases levels of mature HDL-C particles. The first CETP inhibitor to move into clinical trials was torcetrapib (Pfizer, Inc). Despite large increases in HDL-C, development of torcetrapib was terminated due to excess mortality in the torcetrapib group of the large outcomes trial, Investigation of Lipid Level management to Understand its Impact in Atherosclerotic Events (ILLUMINATE). Increased mortality in the torcetrapib-treated group occurred despite a 72% increase in HDL-C and a 25% decrease in LDL-C [8]. Torcetrapib also had no benefit on atherosclerotic progression in two noninvasive imaging studies, despite similar lipid changes [9,10]. The adverse mortality effect of torcetrapib has been largely attributed to accelerated hypertension due to activation of the renin–angiotensin–aldosterone system through a non-CETP-dependent effect [11]. Other mechanisms, such as lack of HDL functionality and proinflammatory effects, have also been proposed to explain torcetrapib’s adverse effects. Two CETP inhibitors are still in development, anacetrapib and dalcetrapib. Neither agent has been found to increase blood pressure or influence the renin– angiotensin–aldosterone axis in studies to date [7]. The more potent CETP inhibitor, anacetrapib, comes from the same chemical class as torcetrapib and strongly binds to the CETP molecule. Added to optimal statin therapy, anacetrapib 100 mg has been shown to increase HDL-C by 138% and reduce LDL-C an additional 40%, with modest triglyceride-lowering effects [12]. The less potent dalcetrapib is from a different chemical class, binds reversibly to and induces a different conformational “Given the excess mortality caused by torcetrapib, it is unlikely that any CETP inhibitor will receive regulatory approval prior to the completion of the long-term cardiovascular end point trials...”