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The Role of Surrogate Markers In The Statin Debate

Cholesterol-lowering therapy sure has been taking a beating lately.  For manysurrogatemarkers.jpeg years, it was accepted that cholesterol medications are good because they reduce “bad” LDL cholesterol.  Over time, lowering LDL would lead to fewer heart attacks and strokes, which is a good thing.  

However, recently some have been preaching against this gospel.  The premise of a widely-cited BusinessWeek article was that statins do little for people without pre-existing heart disease.  

In addition, we have the furor over the ENHANCE trial. Overall, the study failed to show that the combination drug Vytorin had any influence on the build up of fatty plaques in the arteries.  Arterial plaque is a major (and physical) indication that a person is at risk for a heart attack or stroke.

While these studies have generated a lot of attention, what’s more interesting is what they tell us about the ability of surrogate markers to predict death and disease.  Surrogate markers like high cholesterol and hypertension are commonly used to indicate whether a person has a higher risk of dying from heart disease.  However, it is important to note that the relationship between a surrogate marker and the ultimate endpoint of death is often not linear.   


Scientists have long understood that surrogate markers like cholesterol don’t do a very good job of predicting whether someone will die of heart disease or have a stroke.  One famous, but controversial trial, ALLHAT, showed this quite clearly.  In the cholesterol arm of the trial, people taking pravastatin reduced their lipid levels.  However, they were no less likely to have a heart attack or stroke or die than those undergoing “usual care” (who also reduced their cholesterol levels).  

This is why ENHANCE was so important.  If Merck/Schering-Plough could show that cholesterol-lowering therapy impacted a known, physical risk factor for heart attack and stroke, plaque build-up, it would have a stronger case for its medication.  However, even if the medication reduced plaque build up, we still wouldn’t know whether it would have any impact on death and heart disease.  

All of this indicates that we need better surrogate markers.  While cholesterol-lowering therapy benefits people with heart disease, the jury is still out on whether healthier people need statins.  Unfortunately, research on new surrogate markers don’t tell us much about the benefits of statins for those without heart disease.  According to BusinessWeek, Dr. James Liao’s work indicates a “molecule called Rho-kinease is key.  By reducing the amount of this enzyme, statins dial back damaging inflation in arteries . . .The work also offers a possible explanation of why that benefit is mainly seen in people with existing heart disease and not in those who only have elevated cholesterol.  Being relatively healthy, their Rho-kinase levels are normal, so there is little inflammation.  But, when people smoke or get high blood pressure, their Rho-kinase levels rise.  Statins would return those levels closer to normal . . ."

Today, it is unclear how the debate over statins will play out.  However, one thing is true.  If statins benefit people with existing heart disease, we can be sure the numbers of people using them will increase.  The reason: the population is aging and more people are developing heart disease.  These demographic trends may make the argument about statin use in healthier people moot.  

Image Source:  

Image Caption: Cholesterol is transported to the artery wall by LDL and transported from the artery wall back to the liver by HDL. 

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