The follow-up to this week’s Vytorin flap has taken an ominous twist. And I’m not just thinking of threatened investigations and lawsuits. A handful of relatively prestigious publications have moved past criticizing Vytorin, Merck, and Schering-Plough and have begun to ask uncomfortable questions about statins in general and the whole idea of lowering cholesterol. In the process, they’ve put on the table the statistical concept of “number needed to treat” (NNT), which could make life even more difficult for pharma companies.

A New York Times piece by reporter Alex Berenson lays out the basic case: Everyone has always assumed that lowering cholesterol was a good thing, so pharma companies haven’t had to prove that their products actually work, as long as they lower LDL. But the Vytorin ENHANCE trial, as well as the failure of Pfizer’s torcetrapib call that into question.

“The idea that you’re just going to lower LDL and people are going to get better, that’s too simplistic, much too simplistic,” said Dr. Eric J. Topol, a cardiologist and director of the Scripps Translational Science Institute in La Jolla, Calif.

Business Week digs in deeper, mapping out the concept of NNT—the number of patients who need to be treated with a given therapy in order to achieve one cure. And statins, if the story’s sources are to be believed, have a pretty poor NNT. Lipitor, for instance, clocks in at 100. And, according to the story,

Several recent scientific papers peg the NNT for statins at 250 and up for lower-risk patients, even if they take it for five years or more. “What if you put 250 people in a room and told them they would each pay $1,000 a year for a drug they would have to take every day, that many would get diarrhea and muscle pain, and that 249 would have no benefit? And that they could do just as well by exercising? How many would take that?” asks drug industry critic Dr. Jerome R. Hoffman, professor of clinical medicine at the University of California at Los Angeles.

In the long run, it’s probably a good thing for NNT to be part of the public debate on drugs, but the worrisome thing is that the flap over statins might lead FDA to start to reject surrogate endpoints (like lowering LDL cholesterol) and starting to insist on endpoints like mortality in most or all trials. That would be bad for the industry and patients alike.

For another take on cholesterol and NNT check out this editorial from the British Medical Journal.