November 09, 2008
Crestor Cuts Mortality Risks From High hs-CRP Levels

For people with normal cholesterol but high scores in a test for the inflammation marker high-sensitivity C-reactive protein (hs-CRP) the statin drug rosuvastatin (Crestor) very substantially cuts cardiovascular disease risks and mortality risks. So getting an hs-CRP test is a good idea.

Montreal, November 9th 2008 - A team of international researchers including scientists from the McGill University Health Centre (MUHC) and McGill University have discovered that having high levels of particular protein puts patients at increased risk of developing cardiovascular disease. The results of the study were so conclusive that the clinical trial had to be stopped before its scheduled completion date.

Researchers associated with the international JUPITER Project have demonstrated that high levels of high-sensitivity C-reactive protein (hs-CRP) leads to increased risk of cardiovascular disease. This risk decreases by up to 44% if the patients are treated with statin medications.

Dr. Jacques Genest, of the Research Institute of the MUHC and McGill's Faculty of Medicine led the Canadian component of the JUPITER clinical study, which was initiated by Dr. Paul Ridker of the Harvard University Faculty of Medicine.

"The risk of cardiovascular disease due to increased hs-CRP levels has been greatly underestimated until now," according to Dr Genest. "Our results show that this is an extremely important indicator that doctors will have to consider in the future."

"We hope that this study will prompt a review of current clinical practices, especially in terms of screening and prevention in adults," he added. "However, we still need to do more research to establish specific standards."

A 21% decrease in mortality in just a couple of years treatment is impressive.

The JUPITER study included 17,802 patients from 27 different countries. All had normal levels of cholesterol (LDL-c) and high levels of hs-CRP, and according to current standards, were not considered "at risk" for cardiovascular events, and were therefore not receiving any treatment. During the study, participants received a daily dose of the statin drug rosuvastin, and its consequences were striking: a 44% decrease in the risk of cardiovascular disease and a 21% decrease in mortality.

"These results definitely surpassed our predictions," said Dr. Genest. "We had to stop the study before its scheduled completion, as the benefit of the treatment for the selected patients was so great that we needed to present our findings to the medical community as soon as possible."

Since statins have a cholesterol-lowering effect, they are currently used to prevent cardiovascular disease in patients who are at-risk due to high LDL-c levels. But cardiovascular disease is also caused by vascular inflammation, which is marked by levels of hs-CRP. This study shows that statins indeed act on both cholesterol and inflammation, an effect that has long been suspected but not proven.

The study was stopped a few years early because it was so successful.

The researchers planned to follow the subjects for five years, but an independent panel monitoring the study stopped the trial in March after an average follow-up of less than two years, concluding that the benefit was so striking that it would be unethical to continue withholding the real drug from those taking the placebo. But no details were released at the time.

But these results do not prove all cause mortality will be lowered if statins are taken for decades by those with high hs-CRP. Still, these results are very suggestive.

Widespread screening might turn up 6 million Americans who could benefit from statin use due to high hs-CRP.

Dr. Ridker said an analysis by study statistician Robert Glynn of Brigham estimated that applying the Jupiter findings to medical practice for six million Americans for five years would prevent 250,000 major cardiovascular events. The study suggests 25 patients would need to be treated for five years to prevent one major event, a number Dr. Ridker says appears at least as cost effective as strategies screening for high LDL.

Reports of serious adverse events were evenly divided -- 1,352 on the drug and 1,377 on placebo -- as were reports of muscle weakness -- 1,421 on the drug and 1,375 on placebo. Muscle side effects cause some patients to go off statins. There were 270 cases of diabetes among Crestor patients, compared with 216 on placebo.

The higher rate of diabetes among statin users is troubling. Muscle problems and memory problems also show up as side effects. Statins are not risk free. My hope is that cheap widespread genetic testing will eventually allow much more precise targeting of statin use. Those with high genetic risks of side effects will be able to steer clear of statins while those at great risk can know to take the drugs.

Some of you might have read that C-Reactive Protein (CRP) isn't looking as useful for identifying those at risk for heart disease as originally thought. However, this latest study use a more telling CRP test called the highly sensitive C-reactive protein (hs-CRP) assay. This hs-CRP assay sounds like it really picks up on risks that cholesterol tests miss.

C-reactive protein (CRP) is one of the acute phase proteins that increase during systemic inflammation. Its been suggested that testing CRP levels in the blood may be an additional way to assess cardiovascular disease risk. A more sensitive CRP test, called a highly sensitive C-reactive protein (hs-CRP) assay, is available to determine heart disease risk.

What I'd like to know: What diet and lifestyle factors will lower hs-CRP? My guess is all the usual suspects: vegetables, fruits, fish, exercise. Anybody up for some googling (or maybe Pub Med searching) on this question?

Update: Writing in a New England Journal of Medicine editorial Mark A. Hlatky, M.D. observes that long term safety is unproven.

On the other side of the balance, of concern are the significantly higher glycated hemoglobin levels and incidence of diabetes in the rosuvastatin group in JUPITER (3.0%, vs. 2.4% in the placebo group; P=0.01). There are also no data on the long-term safety of lowering LDL cholesterol to the level of 55 mg per deciliter (1.4 mmol per liter), as was attained with rosuvastatin in JUPITER, which is lower than in previously reported trials. Long-term safety is clearly important in considering committing low-risk subjects without clinical disease to 20 years or more of drug treatment. Finally, the cost of rosuvastatin (roughly $3.45 per day) is much higher than that of generic statins.

Update: Stephen Colbert weighs in on the Jupiter Crestor trial:

Well worth a watch.

Share |      Randall Parker, 2008 November 09 08:31 PM  Aging Drugs


Comments
Nick G said at November 9, 2008 9:19 PM:

I would note several things. First, this was funded by the manufacturer, something that is highly correlated with falsely positive drug studies. 2nd, the actual number of heart attacks was reduced by 38 (IIRC). That's less than the number of additional diabetes cases, not to mention other side effects such as coq10 depletion (muscle weakness, serious memory loss, etc) . It looks like a "number to treat" of about 500 - it's not clear where that 25:1 ratio came from - that appears to aggregate a number of smaller things.

I find the suggestion of tens of millions of additional users troubling.

Forrest said at November 10, 2008 3:46 AM:

Coincidentally, just before reading this entry, I had seen a commentary on another site regarding the latest study: http://www.lewrockwell.com/sardi/sardi94.html

Apparently, vitamins C and E each have similar effects in reducing C-reactive proteins as Crestor - with fewer potential side-effects and at much lower cost.

kurt9 said at November 10, 2008 8:23 AM:

The problem with statins is that they inhibit CoQ-10 production, which is an essential feedstock for mitochondrial ATP production. In other words, statins interfere with metabolism, which is the most fundamental biochemical process in the body. Thus, taking a statin is like cutting off your nose to spite your face.

Lou Pagnucco said at November 10, 2008 10:36 AM:

An impressive result.

Regarding VitaminC&E supplementation, this new press release is disappointing:
"Vitamins C and E do not cut heart attack, stroke risk"
http://www.reuters.com/article/healthNews/idUSTRE4A82GD20081109
So, once again, antioxidants fail a crucial test.
Perhaps, though, C+E might work by lowering CRP when coupled with cholesterol lowering therapies?


A quick literature scan show that the following dietary and life style factors reduce CRP -

Various flavonoids, polyphenols, phytosterols, long-chained omega-3 oils (esp., high dose), monosaturated fats,
moderate alcohol consumption, high fiber diets, choline, betaine, vitamin C, low calorie diets, low glycemic index
diets, Mediterranean diet coupled with exercise

The following seem to raise CRP levels-

High glycemic index diets, high caloric diets, eggs, Conjugated Linoleic Acid (CLA), trans-fats, cholesterol, abdominal fat, sedentary life style, chronic systemic disease (esp. periodontal disease), chronic and acute stress, smoking

It is probably also worth noting that low dose doxycyline also significantly reduces CRP.

Randall Parker said at November 10, 2008 5:32 PM:

Lou,

I had you in mind when I asked if anyone would go Googling for CRP-lowering factors. Thanks.

C and E: Keep in mind that only people who have elevated hs-CRP need to lower it in the first place. So the C and E aren't going to help those with low CRP. Also, if people have high cholesterol then lowering CRP probably isn't sufficient.

Things that lower CRP: It is pretty much the standard list of things we already ought to be doing based on many other research reports. More fruits and vegetables will lower one's glycemic index, boost ones flavonoids, boost one's polyphenols and boost C. One can eat good food for phytosterols too. Turns out rice bran oil is highest in phytosterols followed by corn oil, wheat germ oil, flax seed oil, and cotton seed oil. The nuts score high.

Note to self: buy some rice bran oil.

Nick G,

Tens of millions of additional users? I saw 6 million in some of the reports with at most 10 million from one analyst. But that involves a lot more people getting hs-CRP testing in the first place. Personally, I'm just going to tweak my diet to boost the CRP-lowering foods even higher.

Jake said at November 10, 2008 8:01 PM:

Bringing your Vitamin D up to optimum level will reduce both CRP levels and blood pressure.

BDP said at November 10, 2008 10:20 PM:

Generic simvastatin is "way more cheaper" and has a better safety record. There are other products which are effective and safe available for much less than Crestor. Crestor is much more expensive and has a track record of side effects substantially higher than several other similiar drugs unless the dosage is reduced. Simvastatin is the only one that is water soluble and affects the brain. There are surveys/studies that show the incidence of age induced brain deteroriation is substantially reduced with simvastatin. There appears to be little that is unique to Crestor, except that it is the new product on the block and it is available in high strength form. No one is conducting a comparison test with other statins.
The assumption that the results published are unique to Crestor is unknown, until someone conducts similiar testing programs with other products.

They shut the study down early because they got early positive results. Longer use could have shown more problems with more & more serious side effects as time was extended. Such problems are documented as a basis for criticism of Crestor, particularly with higher dosages. The longer the test went the more likely negative findings would be documented. Quit while you are ahead.

Now that some of the leading products are available as low priced generic drugs there is little or no incentive to manufacturers to conduct studies of those low margin products. The odds of there being such a comparison study among competitive products is very small.

Lou Pagnucco said at November 11, 2008 8:29 AM:

Randall,

Regarding rice bran, there are a couple of things worth noting.

Rice bran (less so for other grains) is often very high in arsenic. I am not sure whether extracting the oil removes the arsenic. Also rice bran (and some of the other grain brans) is quite high in phosphate which may cause soft tissue calcification and kidney disease. I wouldn't consume bran for phytosterols without further research. Possibly, the oil is safer, if heavy metal and phosphate content is reduced.

Jake said at November 11, 2008 8:56 AM:

Cardiologists say that it is rare for a person who has elevated CRP not have elevated LDL. So this finding is going to help very few people.

Randall Parker said at November 11, 2008 5:58 PM:

Lou,

I doubt that oils contain arsenic or much phosphate.

Jake,

The estimate is that 6 million might fit this profile of high CRP and lower cholesterol.

Also, I've read the claim that half of all heart attack victims do not have a risk profile based on blood lipids. Anyone know if that is true?

BDP,

I've read that Crestor has a higher frequency of side effects than Lipitor. Don't have a cite for that. Anyone have a good source of info for side effect rates of different statins?

Nick G said at November 13, 2008 9:50 AM:

"Tens of millions of additional users"

The January cover story in BusinessWeek about this (statins and inflamation vs lipids) said that 15M people in the US are on statins, and that official guidelines, if fully implemented, would put about 40M on them.

Randall Parker said at November 15, 2008 8:42 AM:

Nick G,

But to be clear: That 40M is from the existing guidelines, not from this CRP test, right?

Robert Carmichael said at December 23, 2008 4:22 PM:

The supplement that lowers CRP the best for me is magnesium citrate. I take it twice a day.

friedemann said at July 14, 2009 9:51 AM:

Stopping a study prematurely is questionable in itself. The early benefits? Excuse me?
They stopped the testing prematurely with other chemicals because they seemed to have great benefit - chemicals such as DDT, Malithion,
insecticides that were harmful to bugs but not so much to humans. Reported cases where farmers would not only spray their orchards in a T-shirt but would wash their hands off after working on the tractor using DDT as the "washing liquid."
What about CFL's?
A study is a study for a particular length for a reason. Not just to see the benefits, but to find the negative side to it too. They were not testing for negatives which makes the study biased.
That is no different than the judge hearing one side of the story and then making a verdict. Hey, if it is the criminals side of the story, you "know" how he is going to present himself.

Jackie B said at March 31, 2010 10:56 AM:

Hi Folks, I have a high CRP (20.6) and a low-normal LDL (56). I was put on Crestor to lower my CRP. My HDL dropped and my A1C went up. Go Figure...the dosage was low -- I want to say .5 every other day. Now I've dropped to 2X per week.
No one knows the source, but I have arthritis, lots of stress and obese. Thanks for the suggestions.

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