The makers of Vytorin, Merck/Schering-Plough Pharmaceuticals, issued a press release about the the Enhance Study yesterday. The news has triggered a media frenzy.
The NY Times reporting of the story:
Drug Has No Benefit in Trial, Makers Say
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.
The Times reported that, while Vytorin cut "LDL levels by 58 percent, compared to a 41 percent reduction with simvastatin alone," but "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.
(Vytorin is the combination of simvastatin and Zetia.)
In other words, the participants taking Vytorin had 53 ten-thousands of a millimeter more plaque growth than the group taking just simvastatin.
I am always uncomfortable when put in the position of defending a drug or drug company. However, it is patently absurd that this study has generated such attention. I suspect the public and media are waiting for another Vioxx-like debacle, with memories of concealed or suppressed data that suggested heightened heart attack risk that was dismisssed by the drug manufacturer. (That's not to say that the company hasn't been trying to delay or modify the outcome 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.
If we accept the data as reported, however, we might 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? This trial does not answer that question, but does serve to raise some doubt.
Another issue: Heterozygous hypercholesterolemia, and thereby LDL cholesterol, may not be the overwhelming 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. Some other factor(s) needs to be present. I would propose that it is the size of the LDL particle: When small, heart disease develops; when large, heart disease is less likely to develop. This issue was not addressed by this study. Readers of The Heart Scan Blog know that conventional LDL cholesterol, the number used in this study, is a virtually worthless number for truly gauging plaque behavior because of its flagrant inaccuracy.
So, there are substantial uncertainties, 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 come to are 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. 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.
As an interesting aside, Dr. Howard Hodis of the University of Southern California and an expert in carotid scanning for heart disease prevention research, made a comment relevant to us in the Track Your Plaque program:
"Clearly, progression of atherosclerosis is the only way you get events,” Dr. Hodis said. “If you don’t treat progression, then you get events."