Vytorin® Crash and Burn? Is cholesterol dead?

Dr. William Davis Health Pro
  • The makers of Vytorin®, Merck/Schering-Plough Pharmaceuticals, recently issued a controversial press release about the Enhance Study that compared the effects of Vytorin® (a combination of simvastatin and ezetimibe, brand name Zetia®) vs. just simvastatin.


    No substantial difference was observed with the addition of Zetia®, perhaps even a negative effect. The news has triggered a media frenzy.

    The New York Times headlined the story, "Drug Has No Benefit in Trial." "Drug doesn't slow artery clogs," declares the Washington Post. A medical marketing website declared "Vytorin study's a stinker." This has been followed by some journalists and scientists calling the entire lipid hypothesis, the notion that high cholesterol forms atherosclerotic plaque and heart disease, into doubt. "New Questions on Treating Cholesterol" (http://www.nytimes.com/2008/01/17/business/17drug.html?ex=1358312400&en=11b68f069a83f57c&ei=5088&par) reads a January 17, 2008 New York Times article.

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    If we follow the logic of the lipid hypothesis, LDL cholesterol reduction is meant to achieve control over atherosclerotic plaque. It then follows that the lower the LDL, the more plaque should be reduced. That means that adding Zetia® to the cholesterol drug simvastatin should further reduce plaque. Since it failed to do so in the Enhance Study, should this challenge the entire hypothesis?


    First, a few details about the Enhance Study:

    The 700 participants in the trial all had a condition called "heterozygous hypercholesterolemia," a genetic disorder that permits very high LDL cholesterols. The average LDL at the start was 318 mg/dl (compared to an average in the U.S. of 132 mg/dl.)

    Vytorin® reduced LDL levels by 58 percent compared to a 41 percent reduction with simvastatin alone. The effects of treatment were compared by ultrasound of the carotid artery. The average thickness of the carotid artery plaque increased by 0.0111 of a millimeter in patients taking Vytorin®, compared to an increase of 0.0058 of a millimeter in those taking only simvastatin. There was no difference in heart attacks or other "events" between the two groups.

    In other words, the participants taking Vytorin had 53 ten-thousands of a millimeter more plaque growth than the group taking just simvastatin. Hardly enough to get excited about.

    But if we accept the data as reported, we might indeed say it calls the entire lipid hypothesis into question: If LDL cholesterol is significantly reduced but is not correlated with reduction in plaque, is LDL the means by which atherosclerotic plaque progresses or regresses? This trial does not answer that question, but does serve to raise some doubt.

    Here's another important (and somewhat technical) issue: Experts in lipids (cholesterol values) generally accept that conventional LDL cholesterol, the number used in this study, is a virtually worthless number, a value that is so inaccurate as to be laughable. LDL is like relying on your busted speedometer to gauge your automobile's highway speed. LDL cholesterol is a deeply flawed measure for gauging plaque behavior because of its inaccuracy. It is therefore difficult to make judgments about differences in plaque correlated to differences in LDL.


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    Even worse, heterozygous hypercholesterolemia, and thereby LDL cholesterol, may not be the driver of plaque growth in this population. It is probably the number of small LDL particles, a factor which is not revealed by LDL cholesterol. For this reason, heterozygous hypercholesterolemia by itself is insufficient to cause heart disease and plaque growth is attributable to something beyond just LDL cholesterol. Some other factor(s) needs to be present. I would propose that it is the number of small LDL particles that determine whether or not plaque growth is impacted: When many small particles are present, atherosclerotic plaque progresses; when large particles are present, atherosclerotic plaque is less likely to develop. This issue was not addressed by this study. Instead, they relied on this flawed measure, LDL cholesterol.

    So, there are substantial uncertainties in the Enhance Study, contrary to the absolute certainty expressed by people like Dr. Steve Nissen (who, by the way, has no expertise in lipoprotein disorders). It is premature to reach any firm conclusions from this study. The only conclusions that I personally reach are to ask 1) Is this yet another reason to question the entire lipid hypothesis as it stands? and 2) What would the results have been had LDL particle number and LDL particle size been examined, not just LDL?

    I would not automatically conclude that Zetia causes carotid plaque. In my view, this is absurd. And I am definitely not one to come to the rescue of a drug or drug manufacturer. I am simply after understanding and truth.


    I am always uncomfortable when put in the position of defending a drug or drug company. However, it is silly that this study has generated such attention. I suspect the media is waiting for another Vioxx-like debacle, with memories of concealed or suppressed data that suggested heightened heart attack risk that was dismissed by the drug manufacturer. (That's not to say that the company hasn't been trying to delay or modify the endpoint of the study, which they apparently have, much to the objections of the FDA.)

    However, at this point, there is no reason to believe that this question possesses any parallels to the Vioxx fiasco.


    Is LDL cholesterol an entirely worthless measure? Is the lipid hypothesis now defunct? I don't think so, but I do believe that our thinking is way overdue for a major overhaul, a revision of the hypothesis. More on that to come.

Published On: January 18, 2008