Monday, December 1, 2008

The fall of cholesterol

The cholesterol theory of heart disease has been getting knocked around a bit these days.

Just writing that sentence feels rebelous. To call cholesterol's causative link with heart disease a theory seems blasphemous. I started thinking about this when I looked over some summaries of the Jupiter data.

The results of the JUPITER trial indicate that rosuvastatin is associated with a significant reduction in major cardiovascular events, including death, in apparently healthy persons with LDL cholesterol less than 130. The reduction in risk was roughly twice as high as one would predict from the reduction in the LDL:
Moreover, the results were quite different from those of trials that recruited on the basis of elevated LDL.

Those trials "generally reported a 20% reduction in vascular risk for each 1 mmol/L (38.7 mg/dL) absolute reduction in the LDL cholesterol level, an effect that would have predicted a proportional reduction in the number of events in our study of approximately 25%," the investigators wrote.

"However, the reduction in the hazard seen in our trial, in which enrollment was based on elevated high-sensitivity C-reactive protein levels rather than on elevated LDL cholesterol levels, was almost twice this magnitude and revealed a greater relative benefit than that found in most previous statin trials," they added.
This mismatch with reduction in LDL and reduction is risk is similar to the findings of with ezetimibe which showed no reduciton in the progression of atherosclerosis despite dramatic reductions in cholesterol.

Add to that the increase rather than reduction in first major cardiovascular events associated with torcetrapib which successfully increased HDL and reduced LDL. Another nail in the coffin also comes with torcetrapib which despite increasing HDL and reducing LDL failed to reduce atheroma volume.

It seems that large swaths of the cholesterol theory need to be revised and updated to account for this new data. While we wait for this new hypothesis it is important to reevaluate all of the conclusions and health recommendations we make based on intermediate end-points rather than on clinical outcomes. The primary health recommendations that I have in my sites are dietary. Low fat diets have repeatedly failed studies on endpoints and are propagated on their ability to improve the lipid profiles. Well, both ezetimibe and torcetrapib improve the lipid profiles and do little else of benefit to patients.

From a 2002 JAMA review:
In the Minnesota Coronary Survey,51 cardiovascular events were not significantly reduced by a high-polyunsaturated-fat diet despite a decrease in serum cholesterol, but the mean duration of dietary intervention was only about 1 year. Two secondary prevention trials testing the approach of total fat reduction did not find a significant reduction in serum cholesterol or CHD events.52-53
A more recent reveiw from Circulation comes to a similar conclusion. It reminds me of a NYT magazine article about the Atkins diet. This wonderful article has a section that looks at the lack of correlation between Heart Healthy diets and actually reducing cardiac events.
It began in January 1977, when a Senate committee led by George McGovern published its ''Dietary Goals for the United States,'' advising that Americans significantly curb their fat intake to abate an epidemic of ''killer diseases'' supposedly sweeping the country. It peaked in late 1984, when the National Institutes of Health officially recommended that all Americans over the age of 2 eat less fat. By that time, fat had become ''this greasy killer'' in the memorable words of the Center for Science in the Public Interest, and the model American breakfast of eggs and bacon was well on its way to becoming a bowl of Special K with low-fat milk, a glass of orange juice and toast, hold the butter -- a dubious feast of refined carbohydrates.

In the intervening years, the N.I.H. spent several hundred million dollars trying to demonstrate a connection between eating fat and getting heart disease and, despite what we might think, it failed. Five major studies revealed no such link. A sixth, however, costing well over $100 million alone, concluded that reducing cholesterol by drug therapy could prevent heart disease. The N.I.H. administrators then made a leap of faith. Basil Rifkind, who oversaw the relevant trials for the N.I.H., described their logic this way: they had failed to demonstrate at great expense that eating less fat had any health benefits. But if a cholesterol-lowering drug could prevent heart attacks, then a low-fat, cholesterol-lowering diet should do the same. ''It's an imperfect world,'' Rifkind told me. ''The data that would be definitive is ungettable, so you do your best with what is available."

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