Cholesterol Drug Studies: Looking At Biomarkers to Evaluate the Effectiveness of Statins & Ezetimibe

Dr. Bill Quick Health Pro
  • 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."
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    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.

  • Now we have to get into a discussion of the end-points that the researchers chose. Rather than using "hard end-points" such as changes in death rates from heart disease, or changes in heart attack and stroke rates, this and many other studies use surrogates for these end-points; the surrogates are "biomarkers." Some of these biomarkers are well-established, and are generally assumed to be valid substitutes for measuring heart attack rates or death rates: for example, lowering LDL-cholesterol has been used as an endpoint in many trials. Using radiologic images to assess disease progression is another biomarker. And one that, in hindsight, may not have been appropriate to assess any difference in the effectiveness of the drugs evaluated in this trial.
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    And the patients chosen may not have been the best group to study: many had been on statins for years, which may have altered the ability of their IMT to change during the study.

    So, how has the scientific community reacted? The ACC pointed out in their statement on the ENHANCE Trial: "There should no be reason for patients to panic. The difference in IMT changes between the simvastatin group and the Vytorin group was 0.006 mm vs. 0.011 mm... Conclusions should not be made until the three large clinical-outcome trials are presented within the next two to three years. The ACC recommends that Zetia remain a reasonable option for patients who are currently on a high dose statin but have not reached their goal. The ACC also notes that Zetia is a reasonable option for patients who cannot tolerate statins or can only tolerate a low dose statin."

    My advice: if you're on Vytorin or Zetia, and and your cholesterol levels have decreased appropriately, you should stay on them; there's no doubt that they can lower cholesterol, which is after all a widely-respected biomarker. One exception: if you have financial issues paying for these drugs, a switch to a generic statin might save money and perhaps have the same effectiveness. Talk it over with your physician.
Published On: April 03, 2008