BusinessWeek Logo
Cover Story January 17, 2008, 10:00AM EST

Do Cholesterol Drugs Do Any Good?

(page 6 of 6)

In an eagerly awaited trial completed in 2006, the companies compared Zetia plus a statin with a statin alone in patients with genetically high cholesterol. But the drugmakers delayed announcing the results, prompting scientific outrage and the threat of a congressional investigation. The results, finally revealed on Jan. 14, showed the combination of Zetia and a statin reduced LDL levels more than the statin alone. But that didn't bring added benefits. In fact, the patients' arteries thickened more when taking the combination than with the statin alone. Skip Irvine, a spokesman for the joint venture, says the study was small and insists there's a "strong relationship between lowering LDL cholesterol and reducing cardiovascular death."

IRRELEVANT LDL?

If cholesterol lowering itself isn't a panacea, why is it that statins do work for people with existing heart disease? In his laboratory at the Vascular Medicine unit of Brigham & Women's Hospital in Cambridge, Mass., Dr. James K. Liao began pondering this question more than a decade ago. The answer, he suspected, was that statins have other biological effects.

Since then, Liao and his team have proved this theory. First, a bit of biochemistry. Statin drugs work by bollixing up the production of a substance that gets turned into cholesterol in the liver, thus reducing levels in the blood. But the same substance turns out to be a building block for other key chemicals as well. Think of a toy factory in which the same plastic is fashioned into toy cars, trucks, and trains. Reducing production of the plastic cuts not only the output of toy cars (cholesterol) but also trucks and trains. In the body, these additional products are signaling molecules that tell genes to turn on or off, causing both side effects and benefits.

Liao has charted some of these biochemical pathways. His recent work shows that one of the trucks, as it were—a molecule called Rho-kinase—is key. By reducing the amount of this enzyme, statins dial back damaging inflammation in arteries. When Liao knocks down the level of Rho-kinase in rats, they don't get heart disease. "Cholesterol lowering is not the reason for the benefit of statins," he concludes.

The work also offers a possible explanation of why that benefit is mainly seen in people with existing heart disease and not in those who only have elevated cholesterol. Being relatively healthy, their Rho-kinase levels are normal, so there is little inflammation. But when people smoke or get high blood pressure, their Rho-kinase levels rise. Statins would return those levels closer to normal, counteracting the bad stuff.

Add it all together, and "current evidence supports ignoring LDL cholesterol altogether," says the University of Michigan's Hayward. In a country where cholesterol lowering is usually seen as a matter of life and death, these are fighting words. A prominent heart disease physician and statin booster fumed at a recent meeting that "Hayward should be held accountable in a court of law for doing things to kill people," Hayward recounts. NECP's Cleeman adds that, in his view, the evidence against Hayward is overwhelming.

But while the new analyses may rile those who have built careers around the need to reduce LDL, they also point the way to using statins more effectively. Surprisingly, both sides in the debate agree on the general approach. For anyone worried about heart disease, the first step should always be a better diet and increased physical activity. Do that, and "we would cut the number of people at risk so dramatically" that far fewer drugs would be needed, says Krauss. For those people who still might benefit from treatment, a recent analysis by Hayward shows that statins might better be prescribed based on patients' risk of heart disease, not on their LDL cholesterol levels. The higher the risk, the better the drugs seem to work. "If two patients have the same risk, the evidence says they get the same benefit from statins, whatever their LDL levels," Hayward says.

Ways to fine-tune this approach may be coming soon. The company that first sequenced the human genome, Celera Group (CRA), has found a genetic variation that predicts who benefits from the drugs. Perhaps 60% of the population has it, says Dr. John Sninsky, vice-president of discovery research, and for everyone else, the NNT is sky-high. "It does not relate at all to your cholesterol level," Sninsky adds.

If the drugs were used more rationally, drugmakers would take a hit. But the nation's health and pocketbook might be better off. Could it happen? Will data on NNTs, the weak link to cholesterol, and knowledge of genetic variations change what doctors do and what patients believe? Not until the country changes the incentives in health care, says UCLA's Hoffman. "The way our health-care system runs, it is not based on data, it is based on what makes money."

Join a debate about TV drug ads.

Carey is a senior correspondent for BusinessWeek in Washington .

Reader Discussion

 

BW Mall - Sponsored Links