Not everyone is so optimistic, however. Some, such as Kinlay and Mason Freeman, director of the lipid clinic at the Massachusetts General Hospital, think positive results from the JUPITER trial would need to be interpreted cautiously. Freeman believes statins indirectly treat inflammation by reducing cholesterol; he also contends that what JUPITER defines as “average” LDL is now being shown to be too high—and that if statins help those whose levels are average by JUPITER’s standards, it will be because the drugs primarily reduce LDL.

Other drugs being tested target the inflammatory pathway itself. One pathway component, an enzyme called lipoprotein-associated phospholipase A2 (Lp-PLA2), is produced by inflammatory cells involved in plaque development. The same enzyme also binds to LDL, triggers the release of pro-inflammatory molecules and accumulates in human atherosclerotic lesions. Because people with high Lp-PLA2 are more likely to have cardiovascular problems such as heart attacks, in 2002 GlaxoSmithKline began testing darapladib, a drug that inhibits Lp-PLA2. In 959 people with coronary heart disease, darapladib decreased levels of Lp-PLA2 by as much as 66%, and after 12 weeks on the drug, the subjects’ levels of hsCRP and interleukin (another marker of inflammation) were both lower. Researchers hope further trials will determine whether the drug actually reduces heart attacks and strokes.

Like other immune responses, inflammation is intended to protect the body, not harm it. But in addition to contributing to heart attacks and strokes, chronic inflammation has been implicated in the development of many cancers, Alzheimer’s disease and type 2 diabetes. Recent research on breast cancer, for example, suggests that a cytokine known as colony-stimulating factor 1 (CSF-1) may attract macrophages, which produce enzymes that encourage tumor development. In Alzheimer’s disease, atheronals, a newly discovered by-product of inflammation, could be part of a process that results in the misfolding of amyloid beta proteins in the brain.

Inflammation’s link to type 2 diabetes began in 1993, when Gökhan Hotamisligil, then a researcher at the Dana-Farber Cancer Institute in Boston and now at the Harvard School of Public Health, discovered that the fat tissue of obese mice showed heightened levels of an inflammation-promoting cytokine called TNF-alpha, and that TNF-alpha caused insulin resistance in the mice, whose cells could no longer efficiently use the glucose they needed for energy (such resistance is a precursor to type 2 diabetes). Hotamisligil then found that the inflammatory response actually originated in the fat cells themselves. “Obesity is like an injury to fat tissue,” he says. When fat cells are continually bombarded with nutrients, they seem to lose the ability to distinguish bad from good. Sensing they’re under attack, the cells produce inflammatory cytokines and activate whole inflammatory networks.

Another connection between inflammation and type 2 diabetes was forged in 2001, when Aruna Pradhan, then working in Ridker’s laboratory at Brigham and Women’s Hospital, and her colleagues sought to discover whether hsCRP was as accurate a predictor of type 2 diabetes as it was of cardiovascular disease. Pradhan tested hsCRP levels in 550 healthy women and found that those with high CRP levels had a fourfold greater risk of developing type 2 diabetes than people with low levels.

That chronic inflammation has taken on such a negative role in diabetes and other diseases seems to be a matter of evolution gone awry. Tens of thousands of years ago, people evolved immune defenses against otherwise deadly diseases and infections, and the people with the best defenses survived to pass on their genes. Now, Ridker says, that process is fighting our modern environment of unhealthy foods, smoking and lack of exercise, causing chronic disease. The solution may be accepting inflammation’s new role as a risk factor, testing for the condition and responding with statins, newer drugs, more exercise and better nutrition.

And though there are many who argue against widespread testing (contending that screening for hsCRP is difficult because a cold or other infection can temporarily raise its value, and that if only a few people will be helped, it doesn’t make sense to screen everyone), Ridker is hopeful that JUPITER’s results may help establish the value of knowing hsCRP levels as a way to reduce the chance of “surprise” heart attacks in people who otherwise seem to be at low risk. “If the JUPITER trial shows that patients with high hsCRP live longer with statins,” he says, “as many as 100,000 heart attacks a year could be prevented.”

  Dossier

1. “Inflammation, Aspirin and the Risk of Cardiovascular Disease in Apparently Healthy Men,” by Paul M. Ridker et al., The New England Journal of Medicine, April 3, 1997. The first paper to show that otherwise healthy people with slightly elevated inflammatory markers are more likely to have heart attacks years later.

2. “Statins for Atherosclerosis—As Good as It Gets?” by Michael R. Ehrenstein, Elizabeth C. Jury and Claudia Mauri, The New England Journal of Medicine, Jan. 6, 2005. This editorial explains the possible reasons why statins reduce inflammation.

3. “Dietary Factors That Promote or Retard Inflammation,” by Arpita Basu, Sridevi Devaraj and Ishwarlal Jialal, Arteriosclerosis, Thrombosis and Vascular Biology, May 2006. A comprehensive analysis of studies examining which foods (antioxidants) soothe and which foods (saturated and trans fats) stoke our internal inflammation.