A study presented at the American Heart Association Scientific sessions shows that the use of the medication evacetrapib alone or in conjunction with statin drugs was linked to a considerable increase in high-density lipoprotein cholesterol (HDL-C) and decreases in low-density lipoprotein cholesterol (LDL-C) amongst patients with sub-optimal LDL-C or HDL-C. The study is published in the Nov. 16 issue of JAMA, as a theme issue on cardiovascular disease.

At present cardiovascular disease is the leading cause of death. Background data in the study indicates:

“Accordingly, considerable efforts have focused on development of novel therapeutic agents designed to address residual cardiovascular risk. Because individuals from the general population with elevations of HDL-C have a reduced incidence of coronary heart disease, it has been assumed that finding an appropriate therapy to increase HDL-C levels would yield substantial clinical benefit.

However, development of drugs that increase HDL-C levels has been challenging and fraught with failures, including the premature termination of a large outcomes trial studying the effects of the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib. Despite failure of the first drug in the class, considerable interest remains in CETP inhibition as a therapeutic strategy, by virtue of the ability of these agents to substantially increase HDL-C levels and, in some cases, reduce LDL-C levels.

Few studies have documented the efficacy and safety of CETP inhibitors in combination with commonly used statins.”

In order to assess the biochemical effectiveness, tolerability, and safety of the CETP inhibitor evacetrapib alone or in conjunction with statin agents commonly used in clinical practice in individuals with dyslipidemia, Stephen J. Nicholls, M.B.B.S., Ph.D., of the Cleveland Clinic, and his team conducted an investigation from April 2010 to January 2011 at academic and community centers in Europe and the U.S..

398 individuals with raised LDL-C or low HDL-C levels participated in the randomized controlled trial and were randomly assigned to groups:

  • 38 participant received placebo
  • 40 participants received 30 mg daily of evaceptrapin alone
  • 39 participants received 100 mg daily of evaceptrapin alone
  • 42 participants received 500 mg daily of evaceptrapin alone
  • and 239 received statin therapy (simvastatin, 40 mg daily; atorvastatin 20 mg daily; or rosuvastatin, 10 mg daily) with or without evacetrapib, 100 mg daily.

56% of participants were women and the average age among patients was 58 years. The initial outcomes measured were percentage changes in LDL-C and HDL-C levels at the start of the study to after 12 weeks of treatment.

At the start of the investigation the average lipid levels were 55.1 mg/dL for HDL-C and 144.3 mg/dL for LDL-C. The team discovered that alone, evacetrapib produced dose-dependent increases in HDL-C of 30.0 to 66.0 mg/dL (53.6% to 128.8%) in comparison with a decrease with placebo of -0.7 mg/dL (-3.0%) as well as decreases in LDL-C of -20.5 to 51. mg/dL (-13.6% to -35.9%) and with placebo -0.7 mg/dL (-3.0%) in comparison with an increase with placebo of 7.2 mg/dL (3.9%). They found that among participants with lower levels of HDL-C or higher triglyceride levels at the start of the investigation the HDL-C changes were considerably greater.

HDL-C levels increased by 42.1 to 50.5 mg/dL (78.5% to 88.5%) when 100 mg/d of evaceptrapib was taken in conjunction with statin therapy and produced greater reductions in LDL-C (-67.1 to 75.8 mg/dL [ -11.2% to -13.9%]) and non-HDL-C in comparison with effects seen with statin therapy alone. The researchers discovered that the combination of statin and evaceptrapib produced greater reductions in LDL-C but no greater increase in HDL-C, compared with evacetrapib alone and was consistent with known lipid effects of statins.

Between participants who received evacetrapib and those in the control groups who received either evacetrapib alone or combined with statin, there was no difference in regards of discontinuation rates or treatment-related side effects.

The researchers explain:

“These preliminary findings suggest that evacetrapib could be administered with statins and may yield potentially clinically important incremental effects on lipoproteins. These results of the current study provide the foundation for a large phase 3 clinical trial designed to assess the efficacy and safety of evacetrapib.”

In an associated report, Christopher P. Cannon, M.D., of Brigham and Women’s Hospital, Boston, comments of treatment methods for individuals with low HDL-C levels:

“Current approaches to patients with low HDL-C levels are, first, institution of therapeutic lifestyle changes with diet and exercise and, if relevant, cessation of cigarette smoking. Each of these approaches has been shown to increase HDL-C and is associated with improved outcomes. The next step is to lower LDL-C. The current guidelines emphasize lowering LDL-C as the primary approach for patients with low HDL-C because it is a proven strategy, and the benefits of lowering LDL-C are present regardless of HDL-C levels (high or low). Next, in selected patients, some lipid experts use currently available therapies including niacin to increase HDL-C levels, although the evidence base for this approach is limited. Further interventions await data from the large randomized trials of current therapies (e.g., niacin) and emerging therapies like the CETP inhibitors, including dalcetrapib, anacetrapib, and, likely, evacetrapib. As such, the quest for the Holy Grail in coronary disease has many worthy knights on the trial.”

Written by Grace Rattue