When the FDA approved the cholesterol-lowering drug Zetia in 2002, there were only handful of clinical trials covering a total of 3,900 patients. None of the patients took the medicine for more than 12 weeks, and the trials offered no evidence that it reduced heart attacks or cardiovascular disease.

This has not stopped doctors from prescribing that drug, either by itself or as a combination medicine called Vytorin. Thanks to extensive consumer advertising, sales of the medicines reached $5.2 billion last year. More than three million people worldwide take either drug every day.

But there is still no proof that the drugs help patients live longer or avoid heart attacks. What’s even worse, there may be a link between the drugs and cancer. Researchers have reported that patients in three clinical trials had a 40 percent higher chance of dying from cancer if they took Vytorin instead of a sugar pill or another medicine.

Merck and Schering-Plough, which jointly make Vytorin and Zetia, strongly defend their medicines. But the questions about Zetia highlights an little-known but crucial flaw in the current drug approval system. Many medicines are approved on the basis of “surrogate endpoints” -- such as proof that they lower cholesterol, rather than proof that they actually reduce the risk of death or disease. But a number of drugs approved this way have recently proved ineffective or even dangerous.