Heart Disease: Not About Cholesterol

[Guest guest]

Wow! Even a friggin' drug company gets it. Of course, the best way to deal with

inflammation is through nutrition and supplements.

April 15, 2008, 12:01AM EST

Heart Disease: Not About Cholesterol?

AstraZenaca's Crestor study finds that statins may help prevent heart attacks

because they control inflammation, not because they lower cholesterol

by Carey

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The idea that lowering cholesterol is the key to preventing heart attacks and

cardiovascular disease has taken a couple of big hits recently. The first came

on Mar. 30, when a panel of cardiologists recommended that Zetia and Vytorin,

cholesterol-lowering drugs marketed by a joint venture of Schering-Plough (SGP)

and Merck (MRK), be used only as a last resort. The reason: A clinical trial

adding Zetia to other cholesterol-reducing drugs had failed to show a benefit

(BusinessWeek.com, 3/31/08).

But in the furor over Zetia and Vytorin, an equally dramatic but largely

unnoticed development occurred the next day. On Mar. 31, AstraZeneca (AZN)

announced that it was halting early a 15,000-patient trial of its

cholesterol-lowering drug, Crestor-because the drug was working better than

expected. The surprising twist: When the patients started taking the drug, their

" bad " cholesterol levels were already very low-so low, in fact, that drugs

normally would not have been recommended or used. Yet patients on the drug had

fewer heart attacks than those untreated in the trial, which was dubbed Jupiter,

and the benefit showed up much earlier than expected. " It was stunning to have

Jupiter stopped so early, " says Dr. Liao, a researcher in the vascular

medicine unit of Brigham & Women's Hospital in Cambridge, Mass., the lead

research center for the trial. " It suggests a new paradigm. These drugs may be

working in ways other than lowering cholesterol. "

That's a heretical notion, given the overwhelming message from doctors,

companies, and the media that high levels of bad cholesterol can lead to an

early grave and must be reduced. According to national treatment guidelines,

everyone's LDL (or bad cholesterol) levels should be brought under 130 mg/dL,

and in many cases, lowered as close to 100 as possible.

Nonbelievers

Yet there have always been doubters about the almighty importance of cholesterol

levels, and there is evidence that LDL may be only a part-and a small part-of

the story. Half of all heart attacks and cases of cardiovascular disease occur

in people with normal or even low levels of LDL (BusinessWeek, 1/17/08), for

instance. And the Zetia trial showed that different types of

cholesterol-lowering drugs don't bring the same benefit. In that trial, the

additional LDL reduction from adding a second drug, Zetia, to the standard

statin-type drug, which works differently in the body, seemed not to help

patients.

Dr. Ridker, director of the Center for Cardiovascular Disease Prevention at

Brigham & Women's Hospital and a professor of medicine at Harvard University,

was one of those who thought something else must be going on. The evidence, he

believed, pointed to a major role for inflammation in causing cardiovascular

disease. He became a proponent of testing blood for a biological marker of

inflammation, called C-reactive protein (CRP). Could inflammation be a better

indicator of risk than cholesterol levels, he wondered? Maybe statins such as

Lipitor work, in part, by reducing inflammation.

Ridker convinced AstraZeneca that it was worthwhile for the company to fund a

major trial to test the idea. After all, there was little risk and lots of

potential gain for the Anglo-Swedish drugmaker. Its drug, Crestor, had been late

to the cholesterol-lowering game, and it lagged behind other drugs in the same

" statin " class, such as Pfizer's (PFE) Lipitor. But if the trial showed that

Crestor worked in patients with low cholesterol, then it could reach a wider

market than the other statins. Instead of just selling it to people with high

cholesterol, it might also be used in those with high CRP or other indications

of inflammation even when they had normal or low cholesterol. That's a potential

expansion of the market by some 25 million to 30 million Americans. " The trial

was originally conceived to see how important a factor inflammation is in

cardiovascular disease, " explains AstraZeneca Chief Executive Brennan).

The trial Ridker launched was huge: 15,000 patients with high CRP levels. Their

average cholesterol level: 108, which is very low. Half the volunteers got

Crestor; half got a placebo. Ridker designed the study so that, if the drug

reduced events like heart attacks by 25%, the benefit in those getting the drug

would be noticeable in 3½ years. " Our expectation was that the trial would take

until 2010 or 2011, " says Brennan.

Instead, the benefit was so obvious that the trial was stopped in March, more

than two years early, so that patients getting the dummy pill could also

benefit. Continuing the trial would have been unethical since it would have

denied the benefit to those still on the placebo. The company says it will make

the actual data public this fall at a scientific meeting. But the effect is

surprisingly large. For the reduction in heart attacks to have been seen so

early, the benefit in these patients is as high, or higher, than the benefits

seen in patients who start with high bad-cholesterol levels. The implication is

remarkable: The main reason why blockbuster statins work may not be because they

lower cholesterol, but because they reduce the inflammation that leads to heart

attacks. " I think statins do work, but maybe not because they lower LDL, " says

Liao.

Body Chemistry

Liao's own research has proved that statins have other biochemical effects than

lowering cholesterol. Most important, they reduce the amount of an enzyme called

Rho-kinase. That, in turn, dials back damaging inflammation in arteries. When

Liao knocks down the level of Rho-kinase in rats, they don't get heart disease.

And in new, still unpublished work, he has showed that simply reducing

Rho-kinase in certain immune system cells is enough to reduce heart disease in

rats.

Depending on details of the data from the Jupiter trial, it may be possible for

AstraZeneca to convince the Food & Drug Administration that Crestor should be

approved for people with low cholesterol but high levels of inflammation in

their arteries. That could turn the drug, now a $2.7 billion-a-year best-seller,

into a mega-blockbuster. Without FDA approval, the company can't yet market the

drug for this new use, " but we think it will take the science in a certain

direction, towards inflammation, " Brennan says. A year's supply of the 20mg

Crestor dose used in the Jupiter trial costs just under $1,200 when purchased

online. If just 5 million more people went on the drug, that would represent an

additional $5.2 billion for AstraZeneca-a nearly 200% boost from current sales.

And if 10 million in the potential market expansion of 25 million to 30 million

people were to take Crestor, the company would add some $11.8 billion in

additional annual sales.

One hurdle, however, is exactly how that inflammation should be measured. CRP is

seen as a bit of a blunt instrument, since it varies considerably among people

and requires multiple tests to establish a true reading. The body's immune

system kicks into high gear at the first sign of injury or disease, be it a head

cold or broken bone, and inflammation increases. In addition, Ridker has been

criticized for having patented the test for CRP at the same time that he is

pushing for more widespread testing-a conflict of interest. Others, such as

Liao, believe that other biological substances, such as the Rho-kinase enzyme,

might end up being a better marker.

Either way, the Jupiter trial adds to the growing evidence that the American

obsession with " bad " cholesterol levels may be misplaced. In the coming years,

doctors and patients may become far more concerned with how inflamed our

arteries are.

Carey is a senior correspondent for BusinessWeek in Washington .