The failure of torcetrapib: what have we learned?
The failure of the cholesterol ester transfer protein (CETP) inhibitor, torcetrapib, has led to questions regarding whether the molecule itself or the mechanism of CETP inhibition was responsible for the adverse cardiovascular outcomes. Given the association with increases in blood pressure and plasma aldosterone levels, torcetrapib has been postulated to have adverse 'off-target' effects. In this issue of British Journal of Pharmacology, Forrest and co-workers have elegantly investigated these effects, demonstrating two salient points -- (1) the pressor effect of torcetrapib is independent of CETP inhibition and (2) although associated with hyperaldosteronism, the pressor effect is likely not mediated by hyperaldosteronism. Anacetrapib, by contrast, did not demonstrate any pressor or off-target effects. Despite these findings, it remains to be proven whether the adverse cardiovascular outcomes from torcetrapib were indeed related to the pressor effects and whether CETP inhibition by other agents will result in beneficial clinical outcomes. Yet, the studies of Forrest and co-workers do bring us closer to unravelling the reasons behind the failure of torcetrapib.
Department of Medicine, Robarts Research Institute and Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
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D000450:Aldosterone / Q000097:blood; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000517:prevention & control; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D006929:Hyperaldosteronism / Q000139:chemically induced; D023303:Oxazolidinones / Q000009:adverse effects / Q000494:pharmacology; D011804:Quinolines / Q000009:adverse effects / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D023303:Oxazolidinones; D011804:Quinolines; D000450:Aldosterone; C483909:torcetrapib; C530884:anacetrapib