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

Nov 15, 2011
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Eli Lilly
Date Presented:
01/01/2011
Date Published:
01/01/2011
Date Updated:
11/15/2011
Original Posted Date:
11/15/2011
References

Description:

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.

Hypothesis:

This study was designed to characterize the efficacy, safety, and tolerability of evacetrapib.

Study Design

  • Blinded
  • Parallel
  • Placebo Controlled
  • Randomized
  • Stratified

Patient Populations:

  • 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%

Exclusions:

  • Any clinical manifestation of atherosclerosis
  • Hypertension
  • Hyperaldosteronism
  • Uncontrolled diabetes
  • Significant liver, kidney, cardiac, or neuromuscular disease

Primary Endpoints:

  • Percent change in HDL-C
  • Percent change in LDL-C

Drug/Procedures Used:

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.

Principal Findings:

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.

Interpretation:

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.

References:

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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