Why ENHANCE Failed - The Misguided War on Cholesterol

Cholesterol fighters of the world are now doing their best to explain what to them is inconceivable - a study by Merck/Schering-Plough Pharmaceuticals failed to perform as predicted.

In this study they had pitted Zocor® and Vytorin® against the perceived atherosclerotic menace of familial hypercholesterolemia, using relative plaque thickness (IMT) of major blood vessels as their primary indicator of success.

For 24 months they had watched for progress and unhappily had been unable to see a significant difference evolving between the Vytorin® and Zocor® groups.

After behind the scenes' deliberation about the possibility of changing endpoints, with rumors reaching all the way to Congress, finally the lid is off and media feasting has begun. Even some of the ardent supporters of cholesterol lowering drugs attempted to distance themselves from this ENHANCE study with its dependence on direct observation of atherosclerotic plaque.

As most of you may know, Vytorin® is nothing but Zocor® to which has been added Zetia®, a non-statin cholesterol lowering drug, acting on the gut absorption rather than on cholesterol synthesis. They did get much lower LDL cholesterol levels with Vytorin® in this study but it made no discernable difference. The implication is that LDL cholesterol lowering is not the key in atherosclerosis treatment or prevention.

Even the validity of the national cholesterol guidelines and the competence of the men who draw up these guidelines now is called into serious question. This is what is causing great pain among these national and international leaders in the cholesterol war. This should not have happened, they think. They have said for years that LDL cholesterol must be lowered at all costs. This is what we all have been told for decades. Is something wrong here?

What is wrong is that these people with the anti-cholesterol philosophy are far better talkers than listeners. Had they been listening these past 10 years they would know that a growing number of people in the scientific community have been aware for years that cholesterol is irrelevant to the atherosclerotic process. Inflammation appears to be the cause.

Cholesterol is nothing but an innocent bystander drawn into the plaques as part of our natural healing. I have said before that labeling cholesterol as causative to atherosclerosis simply because it is there is roughly equivalent to blaming firefighters for fires because they are always there. For four decades physicians have been bombarded with this drivel. What has confused these statin advocates is the dual nature of statin drug effects on the human body.

Yes, statins are reductase inhibitors that reduce cholesterol synthesis through mevalonate pathway inhibition - unavoidably, statins also must decrease the synthesis of CoQ10, dolichols, selenoprotein and normal phosphorylation at the same time, but that is another story. What we have learned only in the past decade is that statins are also powerful anti-inflammatory agents, exerting this effect via nuclear factor kappa B inhibition. Many now believe it is this anti-inflammatory effect of statins that is beneficial in atherosclerosis control, for atherosclerosis is an inflammatory disease.

The ENHANCE study simply helps to prove the irrelevance of cholesterol. This study shows rather dramatically that 80 mg of Zocor® , however it is combined, is equivalent in effect and the addition of Zetia's® cholesterol reduction does nothing more than sell Zetia®.

Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor

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