After the Coronary Primary Prevention Trial, fittingly published in 1984, showed that cholestyramine, a drug that lowers cholesterol by causing its conversion to bile acids, could reduce the risk of heart attacks, cholesterol was widely villainized as a killer. From then on, the decades-old campaign of the American Heart Association against eggs and butter was vindicated in the press and the FDA began considering any drug that could effectively reduce cholesterol levels in the blood to be a preventer of heart attacks.
In truth, however, the evidence suggests that cholestyramine, while increasing the risk of dying from other diseases, lowers the risk of heart attacks not by lowering "cholesterol" but by clearing LDL from the bloodstream more quickly and thus reducing its interactions with free radicals that can oxidize, nitrate, and glycate it. Thus, the liver takes up healthy LDL and the immune system does not need to come and clean up the mess made by the toxic, damaged LDL. When the immune system has to come clean up such a mess, it forms arterial plaques.
For more information, see "High Cholesterol and Heart Disease — Myth or Truth?"
Nevertheless, the medical community has gone gung-ho not over reducing damage to LDL particles, but over lowering levels of LDL-associated cholesterol.
Thus when ezetimibe was released, a drug that suppresses absorption of dietary cholesterol, the FDA did not ask whether ezetimibe reduces oxidation, nitration, or glycation of LDL, nor did it ask whether ezetimibe can be proven to prevent heart attacks. Instead, it simply approved the drug as prevention for heart disease based on the sole evidence that it lowers cholesterol.
A recent study in the New England Journal of Medicine, however, strongly suggested that ezetimibe does nothing to prevent heart disease. It compared the use of a statin plus ezetimibe to the use of a statin plus the B vitamin niacin. While the ezetimibe combination was 70% more effective at lowering cholesterol than the niacin combination, the level of atherosclerosis diminished in the niacin group and actually increased in the eztimibe group.
This came on the heels of two studies (SEAS and ENHANCE) published in 2008 showing that combining a statin with ezetimibe instead of a placebo had no effect on atherosclerosis or heart attacks, despite lowering LDL-cholesterol.
Mike Mitka, senior staff writer for the Journal of the American Medical Association (JAMA), finally asked some critical questions in this month's issue of JAMA:
Should the FDA be approving drugs (especially those that represent new classes of medications) that satisfy established surrogate markers without demanding immediate postmarketing studies to prove clinical effectiveness? Why are physicians continuing to prescribe a drug whose clinical effectiveness has yet to be shown? And why are not more patients receiving niacin, with its proven effectiveness as an adjunct therapy to statins?Merck makes $4 billion per year from the 9 million people taking ezetimibe alone or an ezetimibe/statin combination.
The FDA approved the drug in 2002. In 2005, the first large outcome trial began. Its results will be available in 2015. If its results are anything like the three smaller trials that have been published recently, physicians may stop prescribing it. In the mean time, Merck will make a whole lot of money.
At least writers in the top medical journals are beginning to ask the tough questions. It's a start.
Read more about the author, Chris Masterjohn, PhD, here.