Torcetrapib in Patients With Below-Average High-Density Lipoprotein Cholesterol Levels - Torcetrapib in Patients With Below-Average HDL-C Levels

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).

Study Design

Study Design:

Patients Screened: 409
Patients Enrolled: 162
Mean Follow Up: 8 weeks
Mean Patient Age: Mean age 47 years
Female: 22

Patient Populations:

Age 18-65 years with low HDL-C levels (<44 mg/dl for men and <54 mg/dl for women) at screening

Exclusions:

Major/unstable concurrent illnesses, lipid-altering therapy 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:

Patients were randomized in a double-blind manner to treatment with torcetrapib 10 (n = 32), 30 (n = 31), 60 (n = 34), or 90 mg/day (n = 33) or placebo (n = 32). Lipid parameters were evaluated every 2 weeks for 8 weeks.

Principal Findings:

At baseline, HDL-C averaged from 37 to 40 mg/dl and low-density lipoprotein cholesterol (LDL-C) averaged from 117 to 128 mg/dl.

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 9.0%, 27.5%, 45.1%, and 54.5% for 10, 30, 60, and 90 mg/day, respectively; p < 0.0001 for all except 10 mg group). Absolute changes in HDL-C were +3 mg/dl in 10 mg group, +10 mg/dl in 30 mg group, +16 mg/dl in 60 mg group, and +21 mg/dl in 90 mg group. Percent reduction in LDL-C was significantly greater in the 90 mg group (16.5% 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, 1.6% (2/129) 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 -0.15 to +1.29 mm Hg for systolic blood pressure and from -0.7 to +0.88 mm Hg for diastolic blood pressure.

Interpretation:

Among patients with below-average HDL-C, 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.

Statins have been shown to significantly reduce LDL-C among a variety of patients. However, therapies targeting increase in HDL-C are fewer and have shown limited success. Torcetrapib has been shown in small studies to increase HDL-C. However, 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. The degree and impact of these changes require further monitoring to fully understand the efficacy and safety profile of torcetrapib.

References:

Davidson MH, McKenney JM, 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. J Am Coll Cardiol 2006;48:1774-81.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Cholesterol Ester Transfer Proteins, Follow-Up Studies, Hyperlipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Quinolines, Apolipoprotein A-I, Apolipoprotein B-100, Blood Pressure, Hypercholesterolemia, Triglycerides


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