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This is one of our periodic Five Year Watch columns, examining whether and why predictions of scientific progress were accurate, or hype.

Five years ago, a new class of cholesterol-lowering drugs was drawing lots of praise, even being called potential “holy grails” in a prominent medical journal.

Those drugs, called cholesteryl ester transfer protein (CETP) inhibitors, have failed in various trials since then. And that disconnect is instructive: It’s what can happen when researchers base claims of effectiveness on outcomes that might not necessarily translate into meaningful gains for patients.

Back in November 2011, Eli Lilly announced promising results in an early trial of its CETP inhibitor, evacetrapib, reporting that it lowered LDL, the harmful form of cholesterol, and raised HDL, its beneficial cousin. Lilly kicked off more studies with the goal of applying for FDA approval.


Well, the company got its findings, but the results, announced in October 2015, were not good. Although evacetrapib does raise HDL cholesterol, it doesn’t seem to reduce the risk of heart attacks, strokes, and other cardiovascular problems — the ultimate reason that patients are advised to lower their cholesterol. Lilly halted the trial early and has since shelved the drug.

Other companies have had similarly catastrophic failures. Pfizer dropped roughly $1 billion trying to bring its CETP inhibitor, torcetrapib, to market, before abandoning it in 2006. Roche bowed out of the race in 2012 after a massive trial of its entry, dalcetrapib, proved a failure.That leaves two companies, Merck and Dezima, with CETP inhibitors in development.


But though the failed clinical trials had much in common, the publicity around them diverged more sharply.

In 2011, when Lilly could have crowed about its positive results, its team was refreshingly demure. When asked if the drug could reduce cardiovascular events, Dr. Stephen Nicholls, a cardiologist at Cleveland Clinic who helped lead the study, said, “In the course of the next five years, hopefully we are going to have the answer to this question.”

Contrast that to what Dr. Christopher Cannon, a Harvard physician who led one of Merck’s studies of anacetrapib, had to say in 2010 about that drug. “Anacetrapib has a knock-your-socks-off effect on HDL and a jaw-dropping effect on LDL,” Cannon said in a press release issued by the American Heart Association.

To his credit, Cannon, who is executive director of cardiometabolic trials at the Harvard Clinical Research Institute, was quick to note in an interview with STAT this week that “we have not seen any clinical benefit” from the drugs. Instead, he said, emerging evidence suggests that “mechanism matters” for LDL — in other words, it’s not how much the blood fat drops but why that’s important for reducing cardiovascular risk.

And that’s at the heart of these drugs’ failures. The CETP story reveals the frequent — and often disappointing — lack of agreement between so-called surrogate markers — changes in cholesterol — and real-life benefits such as fewer heart attacks and strokes. The problem is that, for the purposes of press releases and eye-catching headlines, surrogacy sells.

Drug development is and always will be a risky game. Companies spend — and occasionally lose — billions to make billions more. Cautious optimism probably isn’t the message executives and shareholders want to hear when so much money is at stake.

But it should be.