Heart Disease: Not About Cholesterol?

AstraZenaca's Crestor study finds that statins may help prevent heart attacks because they control inflammation, not because they lower cholesterol

by John Carey

The idea that lowering cholesterol is the key to preventing heart attacks and cardiovascular disease has taken a couple of big hits recently. The first came on Mar. 30, when a panel of cardiologists recommended that Zetia and Vytorin, cholesterol-lowering drugs marketed by a joint venture of Schering-Plough (SGP) and Merck (MRK), be used only as a last resort. The reason: A clinical trial adding Zetia to other cholesterol-reducing drugs had failed to show a benefit (BusinessWeek.com, 3/31/08).

But in the furor over Zetia and Vytorin, an equally dramatic but largely unnoticed development occurred the next day. On Mar. 31, AstraZeneca (AZN) announced that it was halting early a 15,000-patient trial of its cholesterol-lowering drug, Crestor—because the drug was working better than expected. The surprising twist: When the patients started taking the drug, their "bad" cholesterol levels were already very low—so low, in fact, that drugs normally would not have been recommended or used. Yet patients on the drug had fewer heart attacks than those untreated in the trial, which was dubbed Jupiter, and the benefit showed up much earlier than expected. "It was stunning to have Jupiter stopped so early," says Dr. James Liao, a researcher in the vascular medicine unit of Brigham & Women's Hospital in Cambridge, Mass., the lead research center for the trial. "It suggests a new paradigm. These drugs may be working in ways other than lowering cholesterol."

That's a heretical notion, given the overwhelming message from doctors, companies, and the media that high levels of bad cholesterol can lead to an early grave and must be reduced. According to national treatment guidelines, everyone's LDL (or bad cholesterol) levels should be brought under 130 mg/dL, and in many cases, lowered as close to 100 as possible.

Nonbelievers

Yet there have always been doubters about the almighty importance of cholesterol levels, and there is evidence that LDL may be only a part—and a small part—of the story. Half of all heart attacks and cases of cardiovascular disease occur in people with normal or even low levels of LDL (BusinessWeek, 1/17/08), for instance. And the Zetia trial showed that different types of cholesterol-lowering drugs don't bring the same benefit. In that trial, the additional LDL reduction from adding a second drug, Zetia, to the standard statin-type drug, which works differently in the body, seemed not to help patients.

Dr. Paul Ridker, director of the Center for Cardiovascular Disease Prevention at Brigham & Women's Hospital and a professor of medicine at Harvard University, was one of those who thought something else must be going on. The evidence, he believed, pointed to a major role for inflammation in causing cardiovascular disease. He became a proponent of testing blood for a biological marker of inflammation, called C-reactive protein (CRP). Could inflammation be a better indicator of risk than cholesterol levels, he wondered? Maybe statins such as Lipitor work, in part, by reducing inflammation.

Ridker convinced AstraZeneca that it was worthwhile for the company to fund a major trial to test the idea. After all, there was little risk and lots of potential gain for the Anglo-Swedish drugmaker. Its drug, Crestor, had been late to the cholesterol-lowering game, and it lagged behind other drugs in the same "statin" class, such as Pfizer's (PFE) Lipitor. But if the trial showed that Crestor worked in patients with low cholesterol, then it could reach a wider market than the other statins. Instead of just selling it to people with high cholesterol, it might also be used in those with high CRP or other indications of inflammation even when they had normal or low cholesterol. That's a potential expansion of the market by some 25 million to 30 million Americans. "The trial was originally conceived to see how important a factor inflammation is in cardiovascular disease," explains AstraZeneca Chief Executive David Brennan.

The trial Ridker launched was huge: 15,000 patients with high CRP levels. Their average cholesterol level: 108, which is very low. Half the volunteers got Crestor; half got a placebo. Ridker designed the study so that, if the drug reduced events like heart attacks by 25%, the benefit in those getting the drug would be noticeable in 3½ years. "Our expectation was that the trial would take until 2010 or 2011," says Brennan.