Effects of Torcetrapib in Patients at High Risk for Coronary Events

Abstract

Torcetrapib therapy resulted in an increased risk of mortality and morbidity of unknown mechanism. Although there was evidence of an off-target effect of torcetrapib, we cannot rule out adverse effects related to CETP inhibition. (ClinicalTrials.gov number, NCT00134264 [ClinicalTrials.gov].).

The Relationship between Very High Levels of Serum High-Density Lipoprotein Cholesterol and Cause-Specific Mortality in a 20-Year Follow-Up Study of Japanese General Population

“…Abnormal HDL-C function raised by cholesterol ester transfer protein (CETP) deficiency leads to lowering of cholesterol efflux, then reverse cholesterol transport was inhibited 29) . A clinical trial using CETP inhibitor has failed to show the protective effect for CHD, although participants in this study showed an extremely HDL-C elevation almost equivalent to very high HDL-C level in our study 30) . Some previous studies have shown mild inverse or no association between HDL-C concentrations and plasma CETP activity [31][32][33] .…”

Aldosterone Does Not Predict Cardiovascular Events Following Acute Coronary Syndrome in Patients Initially Without Heart Failure

“…The analysis cohort excluded 59 patients who were treated with an aldosterone antagonist either at randomization or during the follow‐up period. Aldosterone was measured in dal‐OUTCOMES because another CETP inhibitor, torcetrapib, had been shown to raise aldosterone levels and to promote hypertension 21, 22. After the independent Data Safety and Monitoring Board determined that dalcetrapib had no effect on aldosterone concentrations, measurements were not performed on subsequent patients enrolled in the dal‐OUTCOMES trial.…”

Cholesteryl ester transfer protein: The controversial relation to atherosclerosis and emerging new biological roles

“…Preliminary human studies were also positive in reducing disease markers (15). In the middle of this decade, the first large scale clinical trial using a CETP inhibitor, torcetrapib, was interrupted earlier than anticipated due to high mortality rates (16). In 2007, about 40 years after the discovery of CETP activity, its molecular structure was finally resolved (17).…”

“…However, the study was interrupted earlier than anticipated because of an excess of deaths and cardiovascular events in the group receiving torcetrapib. Cardiovascular disease, cancer, and infection were the main causes of death, and their rates were 40%, 70%, and 100% higher, respectively, in the torcetrapib group (16). Some adverse effects of torcetrapib, such as hypertension and increased aldosterone levels, are thought to be molecular off-target effects (48).…”

“…In summary, the sepsis related deaths in torcetrapib-treated patients (16), hospitalized patients with reduced CETP (63), and LPS-injected CETP deficient mice (59) comprise a strong set of evidence for the protective action of CETP on acute inflammation that cannot be ignored any longer and must be taken into account in future studies of CETP inhibition.…”