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Torcetrapib in Patients With Below-Average HDL-C on a Background of Atorvastatin - Torcetrapib in Patients With Below-Average HDL-C on a Background of Atorvastatin
Description:
The goal of the trial was to evaluate the safety and efficacy of treatment with torcetrapib, a cholesteryl ester transfer protein inhibitor, in patients with below-average high-density lipoprotein cholesterol (HDL-C) also treated with atorvastatin.
Study Design
Study Design:
Patients Screened: 417
Patients Enrolled: 174
Mean Follow Up: 8 weeks
Mean Patient Age: Mean age 50 years
Female: 20
Patient Populations:
Age 18-65 years with low HDL-C levels (<44 mg/dl for men and <54 mg/dl for women) at screening; and either on statin therapy at baseline or have an LDL-C level >130 mg/dl
Exclusions:
Major/unstable concurrent illnesses, lipid-altering therapy other than statins within 30 days, and LDL-C level ≥190 mg/dl or triglycerides ≥400 mg/dl at screening
Primary Endpoints:
Percent change from baseline in the levels of HDL-C at 8 weeks
Secondary Endpoints:
Absolute changes from baseline in HDL-C and percent changes and absolute changes in LDL-C, triglycerides, and total cholesterol at 8 weeks
Drug/Procedures Used:
Following an 8-week run-in period with atorvastatin 20 mg/day, patients were randomized in a double-blind manner to treatment with torcetrapib 10 (n = 34), 30 (n = 39), 60 (n = 31), or 90 mg/day (n = 33) or placebo (n = 37). All patients were to continue atorvastatin therapy. Lipid parameters were evaluated every 2 weeks for 8 weeks.
Principal Findings:
At baseline, HDL-C averaged from 39 to 42 mg/dl and low-density lipoprotein cholesterol (LDL-C) averaged from 83 to 89 mg/dl at the end of the 8-week run-in phase with atorvastatin therapy.
At 8-week follow-up, the primary endpoint of percent change from baseline in HDL-C was greater in the torcetrapib groups compared with placebo (increase relative to placebo of 8.3%, 23.8%, 33.1%, and 40.2% for 10, 30, 60, and 90 mg/day, respectively; p < 0.0001 for all except 10 mg group). Absolute changes in HDL-C were +4 mg/dl in 10 mg group, +10 mg/dl in 30 mg group, +13 mg/dl in 60 mg group, and +18 mg/dl in 90 mg group. Percent reduction in LDL-C was significantly greater in the 60 mg group (15.7% relative to placebo, p < 0.01) and the 90 mg group (18.9% relative to placebo, p < 0.01). Parameters of change in the ratio LDL-C/HDL-C, ratio apo B-100/apo A-I, and large HDL particles were also improved in the 30 mg and higher groups relative to placebo. There were not significant changes in total cholesterol or triglycerides.
In the torcetrapib groups, 2.9% (4/137) had significant blood pressure increases; no patients permanently discontinued therapy due to blood pressure elevations. The average change in blood pressure using all follow-up measures during the study in the torcetrapib groups ranged from -0.20 to +2.22 mm Hg for systolic blood pressure and from -0.2 to +1.09 mm Hg for diastolic blood pressure.
Interpretation:
Among patients with below-average HDL-C also treated with atorvastatin, treatment with torcetrapib, a cholesteryl ester transfer protein inhibitor, was associated with larger increases in HDL-C at 8 weeks compared with placebo in a dose-dependent manner.
Therapies targeting increase in HDL-C, including niacin and fibrates, have shown limited success. Conversely, statins have been shown to be effective in reducing LDL-C among a variety of patients. Torcetrapib has been shown in small studies to increase HDL-C and minimally decrease LDL-C. In the present study, LDL-C was lowered with torcetrapib despite background therapy with atorvastatin 20 mg in all patients. Larger trials evaluating the clinical effects of torcetrapib are still ongoing.
Additionally, while the overall adverse event profile appears minimal, it should be noted that small blood pressure increases have been reported in recent trials with torcetrapib, including in the present study. The degree and impact of these changes require further monitoring to fully understand the efficacy and safety profile of torcetrapib.
References:
McKenney JM, Davidson MH, Shear CL, Revkin JH. Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels on a background of atorvastatin. J Am Coll Cardiol 2006;48:1782-90.
Keywords: Follow-Up Studies, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Apolipoprotein A-I, Quinolines, Blood Pressure, Heptanoic Acids, Hypercholesterolemia, Pyrroles, Fibric Acids, Cholesterol Ester Transfer Proteins, Apolipoprotein B-100, Niacin, Triglycerides
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