More Bad News on Ezetimibe--So Why Do We Still Take It?

In the past I did several posts on the ENHANCE trial (like, http://brodyhooked.blogspot.com/2008/01/now-that-weve-been-enhanced-whats.html) that showed that ezetimibe (Zetia, Vytorin) was a flop at reducing cholesterol containing plaque within arteries.

The news this week is the New England Journal study--http://content.nejm.org/cgi/content/full/NEJMoa0907569
--in which ironically ezetimibe (Zetia) was stabbed in the back by a competing drug company, Abbott, promoting its own drug, extended-release niacin. A head-to-head trial indicated not only that niacin was better at reducing arterial plaque, but that ezetimibe actually caused plaque to increase at the same time as it was making your cholesterol lab values look better (the same as in the ENHANCE study).

The popular media is full of dire warnings from docs saying, "Just because this trial ended up badly, patients should never stop taking the medicines their physicians prescribed for them." This is despite the fact that no harm has ever been shown to come from abruptly stopping a statin or ezetimibe (which are, after all, designed to prevent fututre events and not to treat an existing disease) that I am aware of; and also despite the overriding fact that ezetimibe was approved for sale in the US despite a complete lack of evidence that it prevented any cardiac events, and based solely on the fact that it lowered cholesterol (LDL) levels by a different mechanism than the statins.

So the various lists are humming with people asking--when ezetimibe was never shown to be useful in the first place, and now has been shown in at least two studies perhaps even to be harmful as well as useless, why are people still taking it and prescribing it?

My own vote for this is the Tyranny of the Numbers.

Over the past couple of decades, Americans (physicians and the public alike) have fallen in love with the idea that you can do a blood test and get a number and it tells you how healthy you are--your cholesterol level, or now the refined version, your LDL. I served on two search committees during my previous academic job for Dean of the medical school, and we asked candidates to tell us how their general health was, and they replied, in a number of cases, without us having asked for that number, by telling us what their cholesterol levels were. As if they could reduce their entire health status to a single number. And these people wanted to be Dean of a medical school for Chrissake.

If you are totally in love with the idea that you can measure a magic number and it tells you that you are healthy, then you are equally in love with any medicine that will make that number better--regardless of what that medicine actually does inside your body. Hence Zetia and Vytorin.

I mention that hunch, in the context of this blog, simply to make the point that drug companies are smart when they market. They know that as powerful a juggernaut as their marketing machine is, they generally cannot make the proverbial silk purse out of the sow's ear (which is what we used to try to do before we decided to put lipstick on the pig). Cliches aside, you cannot make people take a drug when your message arrives completely out of left field and people have no conceptual hook on which to hang it. But if you can tie your message to something people already believe in and cherish, then you can put lipstick on the ezetimibe pig and everyone will invite it to the prom. Almost all effective drug company marketing consists of this clever hitching of the drug company message with some strain of U.S. popular culture that pre-existed the message (even if in an earlier life, drug company marketing may have helped to birth that popular culture phenomenon).

Now That We've Been ENHANCED--What's the Message?

Since I last blogged about the ENHANCE trial:



http://brodyhooked.blogspot.com/2007/12/new-cholesterol-controversies-regaining.html



...the big news of the week, that I'm a couple of days late commenting on, is the mind-numbing flop of the ENHANCE trial. When Merck and Schering-Plough started to do the usual Pharma tapdance, specifically calling in an expert consultant group to change the trial's endpoints before the results were announced (without the supposed principal investigator even being at the meeting), we all started to predict that the study results were not favorable to the companies' drug, and that skullduggery was afoot to re-spin the results to somehow make the sow's ear look like a silk purse. Few of us guessed just HOW totally disastrous the results actually were, as finally revealed this week-- that the drug ezetimibe (Zetia), added to a statin (as in the combination drug Vytorin), not only failed to improve arterial wall plaque in any demonstrable way, but may even have worsened it.



So what can we conclude from this?



First--we have really come a long way since when I first started seriously looking into Pharma issues along about 7-8 years ago. It was not all that long ago when ENHANCE would have fallen in the forest like the proverbial tree that no one ever hears, and the negative data about the drug would never have seen the light of day, period. By contrast, when Merck and Schering-Plough started playing games, the major media were all over them right away. I have no doubt that the unexpectedly sudden and total release of the negative results this week were a calculated decision by the companies, that the truth was bound to come out sooner or later and getting it all over with as soon as possible was their only possible survival tool. So the world is on to the sheninighans of the industry in a way almost unimaginable a few years ago.



Second--I think (as a very definite non-expert in cholesterol metabolism and heart disease) that this also throws a lot of the cholesterol story into doubt. We already know, as per my previous blog post, that statins do not act as we would expect them to, if the most important risk factor for later heart and vessel disease was a high level of serum cholesterol, and that lowering cholesterol (by whatever means) was therefore effective in preventing later disease. Now we have the added evidence that ezetimibe, another drug which is almost guaranteed to lower your cholesterol level by a significant margin if you take it, is either completely unproven as a heart disease preventive, or else in fact is demonstrably useless (if the surrogate markers used in ENHANCE are reliable). Sounds to me like we need to take the entire cholesterol-risk model in for repairs.



Third--and this is related to #2--we need to stand back and appreciate the subtle ways that pharmaceutical marketing (aided and abetted by other sources of irrational thinking in both medicine and in the popular culture) screws over a thoughtful and scientific approach to disease. Only in hindsight can we see how completely physicians in the US were sold a bill of goods about cholesterol. We were convinced, not simply by company reps but also by official guidelines, by tons of CME conferences, and you name it, that the secret of being a Good Doc is to measure everyone's cholesterol level, and then try to get it down within the pre-set target ranges, whether we tried to do that first with life style changes and only reluctantly added drugs later (the Really Good Doc), or went to drugs right off the bat (the Not Quite So Good Doc). We can now see that in all likelihood, this strategy is nearly worthless when it comes to preventing serious bad outcomes in our patients or extending their lives. But we can also see that it sure sold a whole sh*tload of drugs for the industry. In short, the have-your-cholesterol-level-checked model of preventing heart disease functioned much like the serotonin-deficiency model of depression--excellent for selling drugs, even if the final scientific evidence shows that it is a myth. When they come to write the history of medicine in the last decades of the 20th century, how much of our "science" is going to go onto the trash heap for this reason?



Now-- I just said that we cannot blame the industry solely for this debacle, that other sources of irrationality also played a role. Just what did I have in mind? How about American physicians' tendency on the one hand to rail against so-called "cookbook medicine" when ever some expert wants them to follow evidence-based guidelines, and yet secretly in their heart of hearts to yearn above all else for a cookbook that tells them how to practice medicine? (Who could write a better cookbook than the NCEP cholesterol guidelines?) How about the American public's deep yearning for the magic pill that will allow us to have the double cheeseburger with fries and escape the consequences?



Berenson A. Cholesterol drug has no benefit in trial. New York Times, Jan. 14, 2008.