January 2008

An Explanation of the Current Controversy about Cholesterol Reducing Medications

By the early 1950's, it was becoming clear that the slabs of fatty material found in the arteries of adult’s hearts were not healthy. The material impeded the flow of blood, and enough of it could block an artery entirely and cause a heart attack. Cholesterol was a significant component of this material, called plaque, but it was not clear whether high blood levels of cholesterol contributed to its formation. Nonetheless, people began to look at blood cholesterol with suspicion.

In part to clarify the role of blood cholesterol in plaque formation, the NIH funded the Framingham Heart Study, which monitored thousands of people’s cholesterol levels and health status over time. In 1977, when research data from the study was analyzed, it came as a surprise that, in men and women over 50, total cholesterol was not a risk factor for coronary heart disease.

There was an interesting explanation for the surprise. Cholesterol is carried around in the bloodstream encased in a protein shell. Since cholesterol is a fat, the protein shell is called a lipo (= fat) protein. There are two kinds of lipoproteins - low density ones (LDL’s), that carry cholesterol to the body organs, and high density ones (HDL’s), that remove it from the body organs and bring it to the liver to be excreted or recycled.

The Framingham Study found that higher than average levels of LDL (carries cholesterol to organs) contributed to the risk of heart attack while higher than average levels of HDL (takes it from organs) lowered cardiac risk. (Mnemonic: it’s good to get a high score on high density lipoprotein.) The reason the total cholesterol levels were relatively meaningless was that high levels could be caused by high levels of cholesterol encased in LDL - which is bad- or by high levels of cholesterol encased in HDL - which is good. (The cholesterol in each of them was identical.)

A few years ago family of drugs called statins were found both to reduce LDL-cholesterol and reduce the frequency of heart attacks. The statins, including Lipitor and Zocor (see end of article for full list), quickly became the largest selling drug category in the world with annual sales of $40 billion. Naturally, companies making other drugs wanted to get into this market. Some of them developed other kinds of drugs (not statins) that reduced LDL, and the FDA approved them for sale.

But just because people who took a drug that lowered LDL got fewer heart attacks doesn’t mean necessarily that all drugs that lower LDL’s will reduce the frequency of heart attacks. Maybe the statins lower the heart attack rate by some other mechanism, like reducing inflammation, or by keeping artery walls healthy in some yet undetermined way, or by reducing some subset of particularly noxious LDL’s. Maybe other LDL lowering drugs won’t prevent heart attacks or might even have some negative effect that outweighs the positive effect on LDL’s.

Despite this uncertainty, the FDA’s has been approving and pharmaceutical companies have been selling new drugs that reduce LDL but have not been proven to reduce heart attacks or overall mortality. That this may be a mistake was highlighted by experience with one new drug that lowered LDL and raised HDL yet seemed to increase the incidence of heart attacks and strokes. Another drug made up of a statin plus a non-statin LDL-lowering drug was found to lower LDL much more than did either of them alone but may have caused more plaque. The drug companies selling the non-statin drugs have promised the FDA to do studies to determine whether their drugs actually lengthen people’s lives. But the FDA has historically put little pressure on the companies to keep their promises and actually carry out these studies, and most have not.

So, what seems certain: Statins lower LDL’s and also reduce the incidence of heart attacks and prolong life. (Currently available statins include Lipitor, Lescol, Lovastatin or Mevacor, Altoprev, Pravastatin or Pravachol, Rosuvastatin Calcium or Crestor, and Simvastatin or Zocor.)

All drugs that lower LDL’s may not prevent heart attacks. Specifically, non-statins and medications that combine a statin with a non-statin have not yet been shown to reduce the frequency of heart attacks or prolong life.