Cholesterol Drug Tackles Inflammation--or Does It?

A powerful cholesterol drug cuts the incidence of heart attack and stroke in half when given to people with high levels of inflammation, according to a new clinical trial. The results have garnered much attention because the people participating in the study have normal cholesterol levels and thus wouldn't be recommended cholesterol-lowering drugs. But the long-awaited trial, called JUPITER, also comes with footnotes; most importantly, no one knows why the drug, Crestor, actually helped these people, and whether and how it should change disease-prevention strategies.

Led by Paul Ridker, a cardiologist at Brigham and Women's Hospital in Boston, the JUPITER trial recruited nearly 18,000 people who had normal cholesterol levels and moderate or high levels of C-reactive protein (CRP), a marker of inflammation in the blood. For about 2 years, half received Crestor, a potent cholesterol-lowering drug in a class known as statins, and half got a placebo. The trial was stopped in March, 3 years ahead of schedule, because Crestor was working so well. Those who took it had about 50% fewer heart attacks and strokes, and their overall death rate was 20% lower than in the placebo group. In absolute numbers, though, the differences were fairly small: 1.8% of those taking the placebo, or 157 people, had a "cardiac event" during the study, compared to 0.9%, or 83 people, taking the drug. The drug also increased the risk of diabetes somewhat.

Crestor lowered LDL, or "bad" cholesterol, by an average of 50% and CRP by 37%, the researchers running JUPITER reported 9 November online in the New England Journal of Medicine and at the American Heart Association meeting in New Orleans.

The trial "challenges ... how we do prevention," says Ridker. The fact that patients with high CRP benefited from Crestor--much like those who take the drug for high cholesterol--means that doctors can use CRP levels to pinpoint those at risk who now sail under the radar, he says. That could help reduce the number of heart attacks and strokes in people with healthy cholesterol levels.

Others believe the picture is more nuanced and that CRP may be less important than JUPITER suggests. For example, no one knows whether the benefits from JUPITER were due entirely to lowering LDL cholesterol, which has long been shown to prevent cardiovascular disease, or from lowering both LDL and CRP. "We know there's a straight line from LDL cholesterol to cardiovascular risk," no matter what the starting number, says Mark Pepys of University College London, who has studied CRP for decades. LDL came down about 50% in JUPITER--a drop that is consistent with the 54% reduction in heart attack that was observed, Pepys says. While study participants were described as healthy volunteers, most were also overweight, 15% were current smokers, and 40% had metabolic syndrome. These risk factors, and not CRP, may explain why having more aggressive cholesterol-lowering goals can help.

Regardless, JUPITER confronts a problem with which cardiologists have wrestled for some time that has nothing to do with CRP: how to treat patients who have normal cholesterol but some common risk factors, such as high blood pressure or obesity. Should these people be on statins, too, aiming for even lower cholesterol? "I think [JUPITER] expands the thinking about risk factors," says cardiologist Benjamin Scirica of Brigham and Women's Hospital, who was not involved in the trial. Scirica, for one, says that JUPITER "brings the target goal down for everybody" when it comes to cholesterol, and he expects to treat cholesterol more aggressively now than he used to.

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