JUPITER Trial Emphasizes the Role of Oxidative Degeneration in Atherosclerosis

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by Chris Masterjohn

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.

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  1. Should a prior heart patient take statins? 1 silent MI and 2 4x bypasses about 14 years apart. The last was 12 years ago. Male 68 years. In your opinion, and a sketch of your reasoning. I am thinking no, because of age.

  2. Hi Duey,

    Thanks for writing and for your appreciation.

    Statins are directed towards the liver because those less specific to the liver are more toxic. Inhibition of this enzyme in the liver decreases the free cholesterol concentration, which causes the liver to increase expression of the LDL receptor to take in LDL from the blood, thus lowering blood levels.

    HDL can oxidize, and you're right that it should get more attention. I'll try to put something together for a future blog post.


  3. Hey Chris,

    I just now stumbled upon your work and I had a couple questions.

    I always thought that statins competitively inhibited the enzyme HMG CoA reductase and therefore blocked cholesterol synthesis. Does this eventually lead to increase to LDL receptor expression?

    Also, when people say that the PUFAs in LDL get oxidized I always wondered, are there PUFAs in HDL? How come HDL doesn't get oxidized.

    Thanks and keep up the good work.

  4. About 13 years ago my hsCRP was over 13. This was found at a time I was having stents and reblocking multiple times. I then had bypass 9 yrs ago. Through diet and lifestyle changes my hsCRP is now 2.2. Lets see a statin do that! I eat grain free and have leveled out my glucose response with a low carb diet.

  5. Matt,

    Thyroid hormone is necessary for LDL receptor function. With adequate thyroid hormone, LDL is brought efficiently into cells and does not oxidize in the blood. Without it, LDL oxidizes and initiates the atherosclerotic process.

    Bacteria infections by thesmelves cannot cause atherosclerosis, but they can seriously aggravate the effect of oxidized LDL. They can also independently cause other forms of arterial damage that do not resemble atherosclerotic plaque. My “Cholesterol and Heart Disease — Myth or Truth?” article discusses some of the early research on bacterial infections.


  6. Chris,

    I’m currently studying the work of Broda Barnes, a former physician that also had a totally different stance on the development of heart disease and its relation to thyroid function. Mark Starr has recently published a book on “type II hypothyroidism,” and it’s connection to heart disease as well, which I have just read.

    Barnes treated nearly 2,000 patients, and only 4 had heart attacks while under his care, 90% less than what would be expected for a group that size. He was also able to lower cholesterol in his patients extraordinarily fast and eliminate hypoglycemia without any dietary counseling (although he was a strong proponent of a high-saturated fat diet).

    Have you any thoughts on hypothyroidism’s link to heart disease and some of the processes you mention?

    What about chlamydia pneumoniae and heart disease? Could it be that suppressed thyroid, synonymous with poor immunity, allows this invader to penetrate, cause arterial lesions which facilitate the use of cholesterol to do repair work (causing build-up, as well as chronic inflammation and elevated CRP)? Could C. pneumoniae and heart disease be another H. Pylori and ulcers? Your thoughts?

  7. Glad you were able to open the blog to comments. I’m sure you’ll get plenty 🙂

    Interesting about the CRP interaction with the oxidized lipids. Seems like advanced glycated end products should also fit into the picture somewhere too. Any thoughts on that?


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