November 16th, 2011

Evacetrapib – The New Wonder Drug?

Several Cardiology Fellows who are attending AHA.11 this week are blogging together on CardioExchange.  The Fellows include Revathi Balakrishnan, Eiman Jahangir, John Ryan (moderator), and Amit Shah. Read the previous post here. Check back often to learn about the biggest buzz in Orlando.

Stephen Nicholls happily presented impressive safety and efficacy data on the new  CETP inhibitor—evacetrapib—at AHA while the paper was simultaneously released by JAMA.

HDL remains a mystery. Drugs that increase HDL have failed to prove utility above statins alone, as exemplified by the AIM-HIGH results. Torceptrapib, another CETP inhibitor, seemed like a dream drug till it was found to increase mortality. The pressure is now on evacetrapib to hit the game winning home run.

The investigators set up a complicated trial to test tolerability and efficacy of the drug at various doses (ranging from 30 mg/day to 500 mg/d) and in combination with various statins (atorvastatin, rosuvastatin, and simvastatin). Overall, 1154 dyslipidemic patients were screened, and 398 were randomized into ten different groups involving various combinations of statin therapy, evacetrapib doses, and placebo.

The bottom line in terms of efficacy was that evacetrapib showed a solid dose-response effect on both increasing HDL and decreasing LDL at 12 weeks, regardless of whether it was paired with a statin. At the maximum dose (500 mg/day) in the evacetrapib monotherapy group, LDL levels dropped a mean of 51 mg/dL and HDL levels increased a mean 66 mg/dL. Nonetheless, no significant differences in C reactive protein levels was found in any of the groups.

No life-threatening reactions were noted, and no CVD events were reported. Most importantly, no increases in blood pressure or cortisol-related effects—as were reported with torceptrapib—were observed.

Safety is very difficult to sell in such a small trial, but is at least a small step forward. I am looking forward to the next study evaluating outcomes. Given the bad karma of previous CETP contenders, it will be impressive if this drug can live up to the hype. It will also test an important aspect of the lipid hypothesis. Until the results come out, we will wait in suspense…

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