Evacetrapib boosts HDL, lowers LDL levels

AHA Scientific Sessions 2011

ORLANDO, Fla. — Results of a preliminary trial suggest that the experimental drug evacetrapib, administered as monotherapy or in combination with statins, may be a beneficial cholesterol-lowering treatment option.

As monotherapy, the enzyme cholesteryl ester transfer protein (CETP) increased HDL levels from 53% to 128% (30 mg/dL to 66 mg/dL), as compared with placebo, which decreased HDL levels by 3% (-0.7 mg/dL; P<.001). Evacetrapib alone (Eli Lilly) was also associated with decreases in LDL of 13% to 36% (-20.5 mg/dL to -51.4 mg/dL) vs. an increase with placebo of 3.9% (7.2 mg/dL; P<.001). In addition, levels of triglycerides fell 16% at the highest dose of evacetrapib.

In combination with statin therapy, evacetrapib 100 mg produced increases in HDL by 78% to 88% (42.1 mg/dL to 50.5 mg/dL; P<.001) compared with statin monotherapy, and decreases in LDL of 11% to 14% (-67.1 mg/dL to -75.8 mg/dL; P<.001).

Compared with evacetrapib monotherapy, the combination of statin therapy with atorvastatin 20 mg (Lipitor, Pfizer), rosuvastatin 10 mg (Crestor, AstraZeneca) or simvastatin 40 mg (Zocor, Merck) plus evacetrapib resulted in greater reductions in LDL (P<.001) but no greater increase in HDL (P=.39).

When the researchers studied the effects of evacetrapib in prespecified subgroups of patients, they found it had greater impact in those who were younger or started the trial with lower HDL or higher triglyceride levels. "

At the highest dose of evacetrapib, there was up to a 170% increase in HDL in patients with low levels," Nicholls said. "This is very encouraging because these are the first patients we would think of treating with an HDL-raising medication."

Further, the drug had no significant effects on blood pressure, aldosterone or cortisol.

The phase 2 study included 398 patients (mean age, 58.3 years) with elevated LDL or low HDL levels. All participants were randomly assigned to placebo (n=38); daily evacetrapib at doses of 30 mg (n=40), 100 mg (n=39) or 500 mg (n=42); or evacetrapib 100 mg with or without statin therapy (n=239) for 12 weeks. Baseline levels of HDL were 55.1 mg/dL and LDL were 144.3 mg/dL, on average.

"Substantial HDL-raising and, with some agents, incremental LDL-lowering has continued to stimulate interest in the development of CETP inhibitors," Stephen J. Nicholls, MD, cardiovascular director of the Cleveland Clinic Coordinating Center for Clinical Research, said at a press conference. "Elucidating off-target toxicities of torcetrapib had provided ongoing hop that CETP inhibition will be shown to be a cardioprotective strategy. However, ultimately, larger CV outcome trials will determine whether CETP inhibitors will reduce the residual risk observed despite the use of existing therapies." - by Casey Murphy

For more information:

• Nicholls SJ. LBCR.04. Presented at: American Heart Association Scientific Sessions 2011; Nov. 12-16, 2011; Orlando, Fla.
• Nicholls SJ. JAMA. 2011;306:2099-2109.

Disclosure: The study was sponsored by Eli Lilly. Dr. Nicholls reports research support from Anthera, AstraZeneca, Eli Lilly, Novartis, Resverlogix, Roche and LipoScience. Consulting and honoraria were provided by Anthera, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Merck, Omthera, Resverlogix, Sanofi-Aventis, and Takeda.

CETP inhibitors are really the most potent HDL-raising drugs that have been developed, and really afford us the opportunity to test rigorously this hypothesis that raising HDL actually reduces CV risk. One key question for the field is the issue of the degree of CETP inhibition in relationship to CV risk reduction. CETP is complicated. It's not entirely clear that there's a linear association between the magnitude of CETP inhibition and the CV risk reduction. So having another CETP inhibitor that has its own degree of CETP inhibition allows more data points, more opportunity to test this relationship. I think that's a terribly important question, one that hopefully will be addressed with the outcome trial with [evacetrapib].

- Daniel J. Rader, MD
Director of the Preventive Cardiovascular Program
University of Pennsylvania

Disclosure: Dr. Rader reports no relevant financial disclosures.

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