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Study causing some chest pains over cholesterol drug

The real purpose of cholesterol-lowering medications like Lipitor is to reduce atherosclerosis, the buildup of cholesterol within the lining of blood vessels.

Since it's impractical to peek inside blood vessels to see how our treatment is going, we follow serum cholesterol levels instead. They're easy to check, and they've proved to be a reliable indicator for what's happening on the inside. Controlling A seems to lead to good outcome B.

That's why Monday's press release from Schering-Plough Pharmaceuticals, the manufacturer of the cholesterol medication Zetia, came as such a shock to physicians and to the millions of patients taking the drug. The company released data from a self-sponsored, two-year study that followed a group of patients with severe cholesterol problems. The patients took either simvastatin (the generic version of Zocor) or Vytorin, a combination drug produced by Merck that includes Zetia and simvastatin.

Both drugs showed powerful reductions in levels of LDL (the "bad" cholesterol), which fell 41 percent in the group on just simvastatin alone, and 58 percent for those taking the simvastatin/Zetia combination of Vytorin.

The shocker
But researchers also took serial ultrasound measurements of the thickness of atherosclerosis in the participants' carotid arteries, and that's where the surprise came. Despite the drop in LDL levels, both groups showed a slight progression of their atherosclerosis, and those on the combination drug — the more powerful cholesterol-lowering medication — had twice as much thickening (0.8 percent on simvastatin vs. 1.6 percent on Vytorin).

That's not what Schering-Plough Pharmaceuticals or anyone else was expecting to find. But that's what had Dr. Kevin Graham's cell phone abuzz Tuesday. As director of preventive cardiology for the Minneapolis Heart Institute, Graham is a nationally recognized expert on cholesterol and heart disease.

No matter the caller, the question was, "Should patients stop taking Zetia?"

"No, I don't think so — not from what we know now," he told me. "The difference in arterial thickness between the two groups was not statistically significant, and besides, there's an inherent danger in changing your practice based on the release of an abstract [a brief summary of a study] like this. There's still a lot we don't know about the study details, and it's certainly not enough to overthrow four years of clinical experience with the drug."

Although the study was not designed specifically to measure clinical outcomes, Zetia users may be reassured that there were no appreciable differences in cardiovascular events such as heart attacks and strokes in study participants. "There are three large event trials under way involving Zetia, and those should tell us a lot more about this issue," Graham added.

If cholesterol levels are a barometer for the process of atherosclerosis, could they be an imperfect one? Is it conceivable that a drug might lower cholesterol  levels but have little effect on atherosclerosis?

"It's possible, but to this point there's been no big study showing that a lower LDL cholesterol doesn't lower the risk of atherosclerosis. This would be a first," he said. "We do know, however, that some cholesterol-lowering drugs like the statins [Lipitor, Crestor, Zocor] have atherosclerotic benefits that go beyond simply lowering cholesterol, what we call pleiotrophic effects."

The statin drugs were designed only to lower cholesterol; all other effects are incidental, accidental, "pleiotrophic."

More than a plumbing problem
To understand the pleiotrophic effects of statins, one has to understand that atherosclerosis is far more than a plumbing problem. It's not just too much cholesterol clogging up the pipes. Various factors — smoking, diabetes, high blood pressure, saturated fats — damage the lining of our blood vessels, causing inflammation and scarring. That's atherosclerosis. The pleiotropic effects of statins seem to include a soothing effect on the lining of our blood vessels, calming the inflammation.

While the cholesterol-lowering capabilities of these medications are well documented, there has always been the suggestion that some medications have stronger pleiotrophic effects than others, i.e. their clinical benefits seem to outperform their cholesterol-lowering potency. If any of the preliminary data from this Zetia trial holds up, it may be that Zetia lacks pleiotrophic prowess.

What to do in the meantime? We'll know more come March, when the full study is presented at the national American College of Cardiology meeting. That's six weeks away. The study ran for 104 weeks and there were no measurable differences in clinical outcomes over that time. So sit tight.

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Comments (1)

Do we really have to wait years after a drug has been approved by the FDA and released onto market before we find out if it has the desired clinical effect? And that can be different from a biochemical effect! Granted, the statins bring down lipids and change the ratios of some of them. But that would be of little value if some of the statins lack clinical efficacy. And can a physician honestly advise a patient to continue to take these drugs just on the remote chance that some where in the future a desirable effect may be shown? Nobody may benefit. Well, except the pharma industry.