Despite reducing LDL or “bad” cholesterol levels and increasing HDL or “good” cholesterol levels, cholesterol medication evacetrapib did not reduce major cardiovascular events like stroke and heart attack, warns new research.

Drugmaker Eli Lilly and Company discontinued the phase III, multi-center study of the drug in October 2015. And now researchers presenting at the 65th Annual Scientific Session of the American College of Cardiology report they first saw the data behind Lilly’s decision and were stunned by the findings.

“We were certainly hoping for different results, and are trying to understand why we didn’t see a benefit from this drug,” says Dr. A. Michael Lincoff of Cleveland Clinic, adding that the trial raises questions on the benefits of raising HDL and “the future of this class of drugs.”

Dubbed as the ACCELERATE trial, the 12,000-patient study on the drug randomized people high-risk for serious heart problems to receive 130 milligrams of evacetrapib or a placebo every day along with standard therapy.

Those who received the drug saw reduced LDL by 37 percent and increased HDL by 130 percent – but the cholesterol improvements did not translate to reduced cardiovascular death, heart attack, stroke, bypass surgery, or angina-induced chest pain events.

Of the participants, 256 suffered heart attacks versus 255 from the placebo group. Stroke affected 92 patients in the drug group compared with 95 in the placebo group, while 434 taking the drug died from cardiovascular illness – like a stroke or heart attack – versus 444 who took placebo.

Dr. Stephen Nicholls, the principal investigator of the study, considered it “the most mind-boggling” part.

“How can a drug that lowers something that is associated with benefit not show any benefit?” he says, referring to the drop in LDL levels.

Evacetrapib is part of a class of drugs called cholesteryl ester transfer protein (CETP) inhibitors, where previous studies suggested that CETP deficiency offers cardiovascular protection. It disrupts the process that typically transfers cholesterol from HDL to LDL in the body.

Evacetrapib, however, is already the third failed venture using this class of drugs. Torcetrapib from Pfizer showed increased adverse events during phase III clinical trial, while Roche’s dalcetrapib trials were also halted when found ineffective.

Merck and Co. is continuing the development of its own CETP inhibitor, which is now in a 30,000-patient trial set to be completed in 2017. The results of the Lilly drug study as well the two previous drugs’, however, are believed to spell slim chances of success for it.

For Cleveland Clinic’s Dr. Steven Nissen, who co-led the evacetrapib study, these studies serve as a wake-up call and demonstrate the importance of large and high-quality outcome trials. He added that other ways of raising HDL cholesterol might eventually provide benefits.

“Just looking at the effects a therapy has on cholesterol levels doesn’t always translate into clinical benefits,” he says.

Now hopes are also pinned on a class of cholesterol drugs called PCSK-9 inhibitors, which lead LDL to dip to levels never before seen in treatments. The drugs are believed to have the same effect as statins, which cause liver cells to draw out cholesterol.

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