A review argues that the harms of torcetrapib trace to its own tight CETP binding and an aldosterone-like effect, not to CETP inhibition itself (Rom J Intern Med 2010)

Original title: Controversy on high density lipoprotein raising therapy

Rom J Intern Med · 1 January 2010 · 5

Cucuianu M, Brudaşcă I

This review discusses the controversy over HDL-raising therapy after CETP inhibition with torcetrapib produced the most impressive HDL cholesterol increase yet achieved, only for clinical trials to show increased mortality and no reduction in atherosclerosis progression. While some concluded CETP inhibition itself was unfavorable and the drug class should be abandoned, the author argues the harms of torcetrapib were compound specific, tracing them to its especially tight binding to CETP on HDL particles, which blocked both neutral lipid and phospholipid transfer from HDL to other lipoproteins, plus a separate off-target aldosterone-like effect raising plasma sodium and lowering potassium. The review notes mice and rats naturally lacking CETP resist diet-induced atherosclerosis while CETP-rich rabbits are highly susceptible, and that families with deficient CETP activity have shown exceptional longevity, supporting continued development of CETP inhibitors that avoid the specific liabilities of torcetrapib.

Original abstract

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.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.