The most recent widely publicized trial using the cholesterol-lowering statin drugs, the JUPITER trial, has been enthusiastically hailed as a justification for the expansion of these expensive drugs from people with high cholesterol levels to those who have low-grade inflammation but normal cholesterol. The study hardly justifies this enthusiasm. It does, however, provide yet another confirmation that atherosclerosis is a disease of oxidative degeneration.
The New York Times led the way in claiming the study “suggests that millions more people could benefit from taking” the drugs. The claim is rather deceptive. Deeper in the article it quotes experts estimating that “millions” more should be taking the drug in addition to the 16 to 20 million Americans who already do, but that only hundreds of thousands of these would experience any benefit over five years. The authors of the study themselves estimated in the original New England Journal of Medicine article that for every 95 people who took the drug for two years, only one would be saved from a heart attack. The other 94 would have spent a bundle of money, but most of them wouldn't have had a heart attack anyway and the one or two that did have one would suffer the heart attack despite taking the drug.
The monetary cost to the individual, health care system, and the already nearly bankrupt federal government through its prescription drug plan may not be the only cost. The investigators observed “a small but significant increase in the rate of physician-reported diabetes . . . as well as a small, though significant, increase in the median value of glycated hemoglobin,” which is a marker of poor blood sugar control. Although they estimated that the number of people who would need to take the drug in order for a single person to benefit dropped from 95 after two years to 31 after four years and 25 after five years, they also stated that had most of the test subjects been enrolled for this long they may have observed a higher incidence of adverse effects: “Since the median follow-up of subjects was 1.9 years, we cannot rule out the possibility that the rate of adverse events might increase in this population during longer courses of therapy.”
A recent Business Week article, “Do Cholesterol Drugs Do Any Good?”, pointed out that the “number to treat” values for other common drugs are remarkably better than those for statins:
Compare that with, say, today's standard antibiotic therapy to eradicate ulcer-causing H. pylori stomach bacteria. The NNT is 1.1. Give the drugs to 11 people, and 10 will be cured.
So no, this study is not an impressive justification for expanding the use of statins to millions more Americans. But what does it tell us?
The focus of the study was whether people with LDL under 130 mg/dL but C-reactive protein (CRP) above 2 mg/L would benefit from statins. Previous studies had already shown that CRP is an independent risk factor for heart disease, that statins reduce CRP, and that the benefits of statins correlate to the degree to which they reduce CRP. Trials testing statins in people with both low LDL and low CRP have been unsuccessful, so this study tested their efficacy when LDL was low but CRP was high. And it was a success.
The authors offer very little discussion of how CRP fits into the “big picture” of heart disease except to point out that CRP is an inflammatory protein and that heart disease is, in part, an inflammatory disease.
As I have pointed out in my article, “Cholesterol and Heart Disease: Myth or Truth?”, the evidence is against the theory that atherosclerosis is a disease of too much lipid. It is instead a disease of oxidative degeneration of lipids.
If any of what follows is difficult to understand, reading the article I linked to in the previous paragraph should provide the necessary background information to understand it.
CRP binds to the cell wall of gram-negative bacteria and appears to be an important part of the immune system involved in wiping up those bacteria to get rid of them. Part of its mechanism of action appears to be directing the cells that line the blood vessel to make “adhesion molecules” that encourage white blood cells to adhere to the blood vessel lining and swallow the bad guys up. A 2002 study showed that it also binds to oxidized phospholipids present in oxidized LDL and cells that have killed themselves, called “apoptotic” cells.
One of the key events in atherosclerosis is that white blood cells called monocytes swallow up oxidized LDL particles, with elements of these particles then turning on certain genes that cause the monocytes to develop into macrophages and finally into the “foam cells” that characterize atherosclerotic plaque. A 2005 study showed that the binding of CRP to oxidized LDL facilitated its uptake into monocytes.
Statins decrease LDL levels primarily by increasing the liver's expression of the LDL receptor on its surface. For some background on what the LDL receptor does, see my Crash Course on Lipoproteins. In short, in order for cholesterol and fat-soluble nutrients to be delivered to tissues rather than left in the blood to oxidize, LDL receptor expression has to be high. As discussed in Issue #14 of my free newsletter, a genetic mutation that leads to heightened expression of the LDL receptor reduces the risk of heart disease by 88% — nearly abolishing the disease.
Having low expression of the LDL receptor — or low functioning of that receptor, as happens when thyroid hormone levels are inadequate — leaves LDL in the bloodstream to oxidize. This is like taking a bottle of vegetable oil out of the refrigerator, taking the cap off, and letting it sit on the table for a week. It will go rancid. By increasing expression of the LDL receptor, statins can help prevent oxidation.
Statins also increase nitric oxide levels by decreasing the activation of a protein called Rho. Nitric oxide also helps decrease oxidation of LDL.
The JUPITER study provides more confirmation that the beneficial effects of statins are mediated by CRP. Given CRP's role in binding oxidized LDL and facilitating its uptake by the immune system, the study also appears to provide yet more confirmation that atherosclerosis is a disease of oxidative degeneration.
But would I take the statin? No. I would combat inflammation with proper diet and lifestyle. It just isn't worth being one of the 24 or 94 people, depending on which numbers you believe, who don't benefit from the drug for every one person who does, but who nevertheless spend the money — or worse, contribute to the increasing cost of health insurance for everyone else or to the aggravation of the unprecedented deficits of the nearly bankrupt federal government.
Read more about Chris Masterjohn, PhD, here.