Statins and ezetimibe and biomarkers   (April 3, 2008)

Several days, ago, it was discussed in the New Jersey Star-Ledger. Then the New York Times. So I guess it's my turn.

The New Jersey paper frequently reports and editorializes on drug company problems. No big surprise, as many drug companies are in NJ -- including Schering-Plough and Merck, who have had a recent egg-on-their-face episode with delayed reporting of a study involving Vytorin and Zetia. But then the New York Times chimed in the next day (April 2) with an editorial, Overpromoted Cholesterol Drugs. The Times editorialized that "It is distressingly late to be learning that these drugs may provide little or no benefit."

Time to clear up the air... sorry, NY Times, but they do have benefit, although a small study came to inconclusive results about their effects on some biomarkers.

Seems that Schering Plough and Merck have been co-marketing a combination drug for hyperlipidemia, called Vytorin. Vytorin is a combination of two ingredients: Zetia (ezetimibe) and Zocor (simvastatin, a statin) in the same pill. It's a very good drug at lowering cholesterol. And it's a very profitable drug, with 15% of the U.S. market for drugs that lower cholesterol. And (no great surprise), it's a very expensive drug when compared to generic "statins".

But a recently-released and much delayed study, called ENHANCE, has gathered a lot of attention amongst cardiologists and the press. The results of the ENHANCE trial,
have finally been published in the New England Journal of Medicine in an article entitled Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia, and have been presented at a recent American College of Cardiology [ACC] meeting.

The authors conducted a double-blind, randomized, 24-month trial comparing the effects of simvastatin either with placebo or with ezetimibe in 720 patients with familial hypercholesterolemia. As expected, the combination of ezetimibe and simvastain proved better than simvastatin alone at reducing cholesterol. But to much surprise, the combination failed to change a biomarker (the growth of fatty plaques in the arteries) any differently than the statin alone, despite dramatic decreases in decreases in levels of LDL-cholesterol and another biomarker (C-reactive protein), where the combination shined compared to the statin alone.

The authors point out that "There are at least three possible explanations for the absence of an incremental reduction in the intima-media thickness [IMT] in patients receiving ezetimibe: the lack of vascular benefit conferred by ezetimibe despite the observed reduction in LDL cholesterol level, the inability of the measurement technique to accurately reflect changes in atherosclerotic burden, and the possibility that the study population had too low a risk, which would limit our ability to detect a differential response to the two interventions."

So, maybe the ezetimibe isn't adding any benefit to the statin. That's been the big play in the media: the combo isn't any better than statin alone. But there are two other equally plausible explanations for the ENHANCE findings: the test was lousy, and the patients weren't appropriately selected.