New Cholesterol Controversies: Regaining Perspective

Cholesterol drugs are making some of the big news this week. First, we read that Pfizer is facing a whistle-blower lawsuit regarding purported off-label marketing of Lipitor--trying to persuade physicians to prescribe the drug for lower-risk categories of patients than officially approved (for a wrap up see the WSJ Health blog, http://blogs.wsj.com/health/2007/12/20/a-jug-of-wine-a-loaf-of-bread-and-lipitor/). Then comes the news that Merck and Schering-Plough, already under fire for the delays in releasing the ENHANCE study of Zetia, have been hit by reports that they also have failed to publish other research showing liver damage in patients taking that drug. The risk is admittedly low, but apparently more than had earlier been admitted (see Berenson in today's New York Times).

It can be a bit challenging to keep all this stuff in perspective--what does it really mean for the treatment of high cholesterol? Here's my view.

Recall that Lipitor, along with Zocor and numerous other drugs, are all "statin" drugs, that reduce cholesterol levels by a mechanism that involves the liver. Zetia is a drug in a different family, that reduces cholesterol by other means. Vytorin is a combination pill that includes Zetia plus Zocor.

Who now is prescribed Zetia? As a rule, two major groups. First, people with high cholesterol but who cannot tolerate taking a statin for any of several reasons. Second, people taking a statin in maximum doses, whose cholesterol levels still remain about the guideline "target"
level, may then have Zetia added to the statin in hopes that two drugs will prove better than one in lowering the cholesterol, as indeed they usually are.

So one naturally wonders, as well as what the risks are for these people taking Zetia, just what benefits they might expect.

For Zetia alone, the answer is pretty clear. There is no evidence whatever, in the long term, that taking Zetia reduces your risks of having a heart attack, stroke, or other bad result from cholesterol messing up your arteries. ENHANCE was supposed to provide a glimmer of such evidence by at least saying what effect Zetia had on plaque inside the arteries, but even that has been held back, leading us to fear that the actual trial results were probably unimpressive. And even plaque thickness is a "surrogate endpoint," not a real outcome of interest such as stroke or heart attack.

So, if Zetia alone has no proof of benefit, what about adding Zetia to a statin? That in turn leads to the question--what evidence is there for giving a statin, and adjusting the doses, based on lab measurements of the patient's cholesterol level?

The majority of patients taking a statin for prevention of bad stuff have no known vessel disease, just a risk for developing it later. (This is called "primary prevention.") There are two physicians who have spent a good deal of effort looking at the statin-primary prevention story. They are James Wright of the Therapeutics Initiative project at the University of British Columbia, a well-staffed and well-respected group capable of doing independent analyses of drug trial data; and John Abramson, author of Overdosed America, who gave up medical practice for several years so that he'd have time to do his own number-crunching on the same data. They published their conclusions recently in Lancet, but earlier work on the statin question can be found at the Therapeutics Initiative newsletter:

http://www.ti.ubc.ca/en/TherapeuticsLetters

I believe that their data are persuasive, especially compared to "official" guidelines written by physicians of whom a majority have financial ties to the pharmaceutical industry, as I describe in HOOKED.

Wright and Abramson point out that there is very weak evidence for statins being good for primary prevention. The data are especially weak for two groups--women, and men over aged 65. Since statins overall are very weak for primary prevention if they work at all, there is little reason to get worried about how much they should lower your cholesterol, or what the ideal target level is that your cholesterol should drop to, or any of the other questions that physicians spend a lot of time obsessing about these days if they follow the official guidelines.

Secondary prevention--taking a statin if you already have known vessel disease, such as a previous heart attack--is quite different. The evidence seems very clearcut that statins really help prevent later heart attacks and strokes in that setting. I would go so far as to say that if I had a heart attack, the very first sip of water I took afterwards, I should be swallowing a statin tablet with, and keep on taking one daily as long as I lived.

So you would think, then, that since statins work for secondary prevention, it would make sense in that group to ask what the target cholesterol should be, or what the ideal dose of a statin is, right? Well, Wright's gang looked at those studies and could not find enough evidence to recommend any given target level to achieve, or any specific dose of statin to achieve it with.

The bottom line seems to me to be:

1. Zetia is unproven for anything of real importance.
2. Statins are of very litttle use for primary prevention. If they benefit anyone, they benefit men below age 65 who also have several other risk factors for cardiovascular disease.
3. Statins are excellent for secondary prevention, but we cannot say what dose you should take, let alone what target cholesterol level to aim for, to maximize that benefit--all we can really say is, take a statin.
4. All this business of checking your cholesterol level, and then adjusting the dose of the statin (or adding a drug like Zetia) if you are not reaching the target, is voodoo. It has basically been made up by well-intentioned "experts" but it is not based on firm evidence.

So if all that is true then we can draw the following conclusions about this recent news:

• There are far too many people already, so far as we know, taking statins; so any marketing that tells us that even more people need to be taking statins is probably a bad thing. (On the other hand, if any people with previous heart attacks, strokes, etc. are not taking statins, they should start.)
• Since there is no known benefit to taking Zetia, any added risk from taking it can hardly be justified.

A couple of footnotes. First, I have said nothing here about how statins compare for either primary or secondary prevention, to lifestyle changes such as diet and especially exercise. Dr. Abramson has some choice words on that subject in his book, and they are not friendly to statins. Second, Alex Berenson in his great NYT article today mentions in passing that when the FDA approved Zetia, they relied on studies looking for possible side effects that lasted, at a maximum, 12 weeks. That is for a drug that is designed to be taken for a lifetime, and where other cholesterol-lowering drugs are known to have side effects that may not show up for months or even years after the drug is started. That fact alone is unconscionable; and shows again how the FDA, at least until very recently, was the industry's lapdog. (And even the 12-week-long studies revealed some concerns about liver damage in people taking Zetia, which was then glossed over!)

Berenson A. Data about Zetia risks was not fully revealed. New York Times, Dec. 21, 2007.
Abramson J, Wright JM. Are lipid-lowering guidelines evidence-based? Lancet 2007; 369:168-9.