ATLANTA — The novel HDL cholesterol-boosting drug torcetrapib, which is being developed solely as a combination pill with atorvastatin, results in favorable lipoprotein changes of unprecedented magnitude, Dr. Tom Thuren reported at the annual meeting of the American College of Cardiology.
He presented data from a multicenter, double-blind, phase II, dose-ranging study involving 493 patients with elevated LDL cholesterol in which torcetrapib 60 mg/day plus atorvastatin 10–80 mg/day—the doses in clinical development—resulted in dose-dependent 44%–66% increases in cardioprotective HDL cholesterol, along with LDL cholesterol reductions of 41%–60%.
The combination of torcetrapib 60 mg plus atorvastatin 80 mg also resulted in a 20% increase in apolipoprotein A-I compared with baseline in the 12-week study. The mean reduction in non-HDL cholesterol was 23% with torcetrapib 90 mg alone, 47% with atorvastatin 80 mg alone, and 61% with the two combined.
Moreover, the various torcetrapib/atorvastatin combinations resulted in salutary changes in lipoprotein particle size as assessed by nuclear magnetic resonance. There was a marked shift away from small, dense LDL particles—the subclass thought to be most highly atherogenic—in favor of large, buoyant LDL particles. Indeed, levels of small, dense LDL cholesterol dropped by 23–70 mg/dL in dose-dependent fashion, whereas large LDL particles increased by 32–68 mg/dL over baseline, noted Dr. Thuren, director of clinical development at Pfizer Global Research and Development, New London, Conn.
Simultaneously, the HDL2 subfraction, which is believed to be particularly cardioprotective, jumped by 79%–198%, whereas HDL3 rose by 22%–45%. HDL particle size increased in a dose-dependent fashion with torcetrapib, but was unaffected by atorvastatin.
Side effects were those associated with statin monotherapy, with one exception: There was a roughly 2-mm Hg increase in systolic blood pressure seen with torcetrapib alone or in combination with atorvastatin.
Torcetrapib is first in a new class of drugs that inhibit cholesterol ester transfer protein (CETP), which is responsible for transferring cholesterol from HDL to LDL.
Although the exuberant lipid changes seen with torcetrapib/atorvastatin in this phase II study are encouraging, what really matters, according to Dr. Thuren, is whether they translate into further reduction in cardiovascular events beyond that obtained with aggressive statin therapy alone. That question is the subject of large, ongoing, phase III, randomized clinical trials.
Pending outcome of these major trials, a new secondary analysis of the landmark Treating to New Targets (TNT) study may provide reason for optimism regarding the potential incremental clinical benefits of coupling HDL cholesterol-raising with LDL cholesterol-lowering.
Dr. Philip Barter presented an analysis of the relationship between cardiovascular events and on-treatment HDL cholesterol levels in TNT, a Pfizer-sponsored, randomized, double-blind study in which 10,001 patients with coronary disease were assigned to 10 mg or 80 mg/day of atorvastatin.
The 80-mg group showed a 22% relative risk reduction in major cardiovascular events compared with those on 10 mg during 5 years of follow-up (N. Engl. J. Med. 2005;352:1425–35).
A patient's HDL cholesterol level remained predictive of cardiovascular event risk both at high and low LDL cholesterol levels, suggesting that HDL cholesterol-raising may be a potential therapeutic target even in patients on aggressive LDL cholesterol-lowering therapy, noted Dr. Barter, professor of medicine at the University of Sydney and director of the Heart Research Institute, Camperdown, Australia.