The risks for cardiovascular events and all-cause mortality were higher with torcetrapib than with placebo in statin-treated patients.
Even in statin-treated patients with low LDL cholesterol levels, low HDL cholesterol remains a risk factor for coronary events (Journal Watch Sep 26 2007). In theory, raising HDL levels ought to prevent cardiovascular events in such patients. That theory was tested in an industry-supported study of torcetrapib, a drug that raises HDL levels by inhibiting cholesteryl ester transfer protein.
The 15,000 study participants had documented cardiovascular disease (82%) or diabetes (18%), and all had LDL cholesterol levels below 100 mg/dL on atorvastatin. They were randomized to receive torcetrapib or placebo; both groups continued atorvastatin. In the torcetrapib group at 1 year, mean HDL cholesterol levels had increased by 72% (from 49 mg/dL at baseline) and mean LDL cholesterol levels had decreased by 25% (from 80 mg/dL). However, the trial was terminated prematurely after a median follow-up of 18 months, when the incidences of cardiovascular events and all-cause mortality were significantly higher with torcetrapib than with placebo. Compared with placebo recipients, torcetrapib recipients had higher blood pressures, higher aldosterone levels, and lower potassium levels.
Comment: Torcetrapib was associated with worse clinical outcomes despite impressively increasing HDL levels in high-risk patients. The authors offer two possible explanations — "off-target" pharmacologic effects of torcetrapib (e.g.,
hypertension and aldosterone excess), and generation of dysfunctional or proatherogenic HDL cholesterol. Whatever the mechanism, these results remind us once again that favorable changes in surrogate endpoints — in this case, HDL cholesterol — do not ensure that favorable clinical outcomes will follow. However, the results do not preclude potential benefit from other HDL-raising therapies.
Published in Journal Watch General Medicine November 29, 2007
Barter PJ et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007 Nov 22; 357:2109.