Lipid-Modulating Effects of Evacetrapib, a Novel CETP Inhibitor, Administered as Monotherapy or in Combination With the Most Commonly Used Statins - Evacetrapib Dose Ranging Study
The goal of the trial was to evaluate treatment with evacetrapib as monotherapy or in addition to a statin compared with placebo among patients with dyslipidemia (high low-density lipoprotein cholesterol [LDL-C] or low high-density lipoprotein cholesterol [HDL-C]).
Evacetrapib is a novel cholesteryl ester transfer protein (CETP) inhibitor.
This study was designed to characterize the efficacy, safety, and tolerability of evacetrapib.
- Placebo Controlled
- Patients at least 18 years of age with dyslipidemia (high LDL-C or low HDL-C) after a dietary lead-in period
- HDL-C <45 mg/dl for men or <50 mg/dl for women OR LDL-C 100-190 mg/dl with 0-1 risk factor, 100-160 mg/dl with ≥2 risk factors and 10-year coronary risk <10%, or 100-130 mg/dl with ≥2 risk factors and 10-year coronary risk 10-20%
Number of screened applicants: 1,154
Number of enrollees: 398
Duration of follow-up: 12 weeks
Mean patient age: 55 years
Percentage female: 53%
- Any clinical manifestation of atherosclerosis
- Uncontrolled diabetes
- Significant liver, kidney, cardiac, or neuromuscular disease
- Percent change in HDL-C
- Percent change in LDL-C
After a 2- to 8-week dietary lead-in period and to allow withdrawal of lipid-lowering therapies, patients with high LDL-C or low HDL-C were randomized to evacetrapib (30 mg, n = 40; 100 mg, n = 39; 500 mg, n = 42) versus placebo (n = 38) versus statin ± evacetrapib (n = 239). The type/dose of statins was simvastatin 40 mg, atorvastatin 20 mg, or rosuvastatin 10 mg.
Overall, 398 patients were randomized. In the placebo group, the mean age was 55 years, 53% were women, mean body mass index was 30 kg/m2, 3% had diabetes, mean blood pressure was 122/77 mm Hg, mean LDL-C was 147 mg/dl, and mean HDL-C was 53 mg/dl.
As monotherapy, the mean change in LDL-C was -35.9% for evacetrapib 500 mg, -22.3% for evacetrapib 100 mg, -13.6% for evacetrapib 30 mg, and 3.9% for placebo. The mean change in HDL-C was 128.8% for evacetrapib 500 mg, 94.6% for evacetrapib 100 mg, 53.6% for evacetrapib 30 mg, and -3.0% for placebo.
As combination with statin therapy, the mean change in LDL-C was -52.3% for evacetrapib 100 mg/rosuvastatin 10 mg, -46.1% for evacetrapib 100 mg/simvastatin 40 mg, and -47.6% for evacetrapib 100 mg/atorvastatin 20 mg. The mean change in HDL-C was 94.0% for evacetrapib 100 mg/rosuvastatin 10 mg, 86.6% for evacetrapib 100 mg/simvastatin 40 mg, and 79.9% for evacetrapib 100 mg/atorvastatin 20 mg.
Blood pressure was similar between the four groups. Drug-related adverse events: 25.0% with evacetrapib 500 mg, 13.2% with evacetrapib 100 mg, 20.0% with evacetrapib 30 mg, and 18.4% with placebo. Elevation in systolic blood pressure ≥15 mm Hg: 20.0% with evacetrapib 500 mg, 13.2% with evacetrapib 100 mg, 23.1% with evacetrapib 30 mg, and 10.5% with placebo.
Among patients with dyslipidemia, evacetrapib as monotherapy or in combination with statins resulted in a marked increase in HDL-C and decrease in LDL-C. The previously studied CTEP inhibitor, torcetrapib, was unsuccessful due to an increase in mortality. There was no increase in blood pressure or apparent adverse events with evacetrapib; therefore, the safety profile of this agent might be different than torcetrapib.
Therapies to safely raise HDL-C to reduce adverse events have remained an elusive target. Future studies to evaluate the clinical effects of evacetrapib are warranted.
Nicholls SJ, Brewer HB, Kastelein JJ, et al. Effects of the CETP Inhibitor Evacetrapib Administered as Monotherapy or in Combination With Statins on HDL and LDL Cholesterol: A Randomized Controlled Trial. JAMA 2011;306:2099-2109.
Presented by Dr. Stephen Nicholls at the American Heart Association Scientific Sessions, Orlando, FL, November 15, 2011.
Keywords: Fluorobenzenes, Benzodiazepines, Follow-Up Studies, Cholesterol, LDL, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Quinolines, Pyrimidines, Risk Factors, Blood Pressure, Heptanoic Acids, Simvastatin, Pyrroles, Dyslipidemias, Cholesterol Ester Transfer Proteins, Body Mass Index, Cholesterol, HDL, Diabetes Mellitus, Sulfonamides
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