New Drug, Evacetrapib, Increases Good Cholesterol, Decreases Bad – Alone or With Statin
The combination of a statin and evacetrapib resulted in greater reductions in LDL but no greater increase in HDL
Nov. 15, 2011 – On the same day
a study was released highlighting the efficiency of two statins to improve cholesterol levels and even reverse artery blockage, another study
finds a new cholesterol fighting drug very effective. The drug evacetrapib alone, or in combination with statin medications, produced
significant increases in HDL (good cholesterol) levels and decreases in LDL (bad cholesterol) levels.
The study was released early online today to coincide with its presentation at the American Heart Association Scientific
Sessions. It will also appear in the November 16 issue of The Journal of the American Medical Association (JAMA), a theme issue on
Cardiovascular disease remains the leading cause of death. "Accordingly, considerable efforts have focused on development
of novel therapeutic agents designed to address residual cardiovascular risk," according to background information in the article.
“Because individuals from the general population with elevations of HDL have a reduced incidence of coronary heart
disease, it has been assumed that finding an appropriate therapy to increase HDL levels would yield substantial clinical benefit.
“However, development of drugs that increase HDL 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 levels and, in some cases, reduce LDL levels
"Few studies have documented the efficacy and safety of CETP inhibitors in combination with commonly used statins."
The biochemical efficacy, safety, and tolerability of the CETP inhibitor evacetrapib as a stand-alone drug and in
combination with statin agents commonly used in clinical practice in patients with dyslipidemia, caught the attention of Stephen J. Nicholls,
M.B.B.S., Ph.D., of the Cleveland Clinic, and colleagues who joined his team to evaluate.
The randomized controlled trial, which included 398 patients with elevated low-density lipoprotein cholesterol (LDL) or
high-density lipoprotein cholesterol (HDL) levels, was conducted from April 2010 to January 2011 at community and academic centers in the
United States and Europe.
Patients were randomly assigned to receive placebo (n=38); evacetrapib monotherapy, 30 mg/d (n=40), 100 mg/d (n=39), or
500 mg/d (n=42); or statin therapy (n=239) (simvastatin, 40 mg/d; atorvastatin, 20 mg/d; or rosuvastatin, 10 mg/d) with or without evacetrapib,
100 mg/d, for 12 weeks. The primary outcomes measured were percentage changes in HDL and LDL levels at the beginning of the trial to after 12
weeks of treatment. The average age of the participants was 58 years, and 56 percent were women.
The average lipid levels at the beginning of the study were 55.1 mg/dL for HDL and 144.3 mg/dL for LDL.
The researchers found that as a single therapy, evacetrapib produced dose-dependent increases in HDL of 30.0 to 66.0 mg/dL
(53.6 percent to 128.8 percent) compared with a decrease with placebo of -0.7 mg/dL (-3.0 percent).
And, it produced decreases in LDL of -20.5 to -51.4 mg/dL (-13.6 percent to -35.9 percent) compared with an increase with
placebo of 7.2 mg/dL (3.9 percent). The HDL changes were significantly greater among patients with lower levels of HDL or higher triglyceride
levels at baseline.
When administered in combination with statin therapy, evacetrapib, 100 mg/d, increased HDL levels by 42.1 to 50.5 mg/dL
(78.5 percent to 88.5 percent).
And, it resulted in greater reductions in LDL (-67.1 to -75.8 mg/dL [-11.2 percent to -13.9 percent)] and non-HDL
compared with effects observed with statin monotherapy.
Compared with evacetrapib monotherapy, the combination of a statin and evacetrapib resulted in greater reductions in LDL
but no greater increase in HDL, consistent with known lipid effects of statins.
There was no difference between evacetrapib and control groups in either the monotherapy or statin combination studies
with regard to the rate of treatment-related adverse events and discontinuation rates.
"These preliminary findings suggest that evacetrapib could be administered with statins and may yield potentially
clinically important incremental effects on lipoproteins," the authors write. "The results of the current study provide the foundation for a
large phase 3 clinical trial designed to assess the efficacy and safety of evacetrapib."
Editorial: High-Density Lipoprotein Cholesterol as the Holy Grail
In an accompanying editorial, Christopher P. Cannon, M.D., of Brigham and Women's Hospital, Boston, comments on treatment
strategies for low HDL levels.
"Current approaches to patients with low HDL 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 and is associated with
improved outcomes. The next step is to lower LDL.
“The current guidelines emphasize lowering LDL as the primary approach for patients with low HDL because it is a proven
strategy, and the benefits of lowering LDL are present regardless of HDL levels (high or low). Next, in selected patients, some lipid experts
use currently available therapies including niacin to increase HDL 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 trail."
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