Decreased
high density lipoproteins (HDL) plasma levels are a recognized independent risk factor for atherosclerotic
cardiovascular disease. Attempts were therefore initiated to pharmacologically raise plasma
HDL cholesterol, and the most impressive increase was obtained by inhibiting
cholesteryl ester transfer protein (CETP) by means of the synthetic compound
torcetrapib. Clinical trials were however disappointing, as
torcetrapib increased mortality and did not reduce the progression of
atherosclerosis. According to some view, it was claimed that CETP inhibition is unfavourable and that development of this class of compounds should be abandoned. Controversy nevertheless stimulated research on HDL structure, heterogeneity and functions which are not limited to reverse
cholesterol transport and exert
antioxidant and antiinflammatory actions. It could also be demonstrated that the deleterious effects of
torcetrapib are compound specific, including its tight binding to CETP on HDL particles, thereby blocking both neutral
lipids and
phospholipid transfer from HDL to other
lipoproteins, and would also exert an off-target effect by increasing plasma
sodium and decreasing potasium concentrations (an
aldosterone-like effect). As the structure of CETP was elucidated, it became possible to design CETP inhibitors that lack such off-target toxicity and may successfully slow the progression of
atherosclerosis. Noteworthy, mice and rats naturally lacking CETP are resistant to diet induced
atherosclerosis, while rabbits with high CETP levels are very susceptible. Families with deficient activity and exceptional longevity had also been reported.