Commentary

Is ezetimibe/simvastatin no better than simvastatin alone? Lessons learned and clinical implications

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The answer may come in 3 to 4 years with the results of IMPROVE-IT, a study of 18,000 patients with acute coronary syndrome treated with ezetimibe/simvastatin or simvastatin. The simvastatin monotherapy group will have a target LDL-C level of less than 80 mg/dL and the ezetimibe/simvastatin group will have an LDL-C target about 15% less. Although this trial is testing the lower-is-better hypothesis with ezetimibe, if the study does not show a benefit, it may not be because ezetimibe lacks clinical efficacy but rather because the LDL-C effect is curvilinear, and there is minimal further benefit of lowering the LDL-C level past 70 mg/dL. If the results of the IMPROVE-IT trial are negative, it may mean the end of ezetimibe as an LDL-C-lowering drug.

Merck/Schering-Plough has lost valuable time in not demonstrating the benefits of ezetimibe on clinical events. In contrast, consider rosuvastatin, an AstraZeneca product. Rosuvastatin was approved about the same time as ezetimibe/simvastatin, and 6 years later it has already received a label change for the reduction of progression of atherosclerosis, based on positive outcomes in the METEOR trial, 35 the ASTEROID intravascular ultrasonography trial, 37 and the CORONA trial (an important trial that examined hard clinical end points). 38 More importantly, the JUPITER trial was recently stopped early owing to a reduction in cardiovascular deaths. Initially, rosuvastatin received an unfair media portrayal as an unsafe drug. Now, because of its proven benefits in outcome trials, it will receive more widespread consideration for clinical use.

For preventive cardiologists, a painful reminder to focus on LDL-C

For the preventive cardiologist or lipidologist, the ENHANCE trial has been a painful reminder that despite overwhelming evidence, the mantra of “the lower the LDL-C the better” is still not universally accepted. We acknowledge the great benefits of statins, but the lure of “pleiotropic effects” distracts many of us from the necessity of more aggressive LDL-C reduction.

The pleiotropic benefits of statins were first raised as a means of supporting increased clinical use of pravastatin vis-a-vis other, more efficacious statins. It was not until the PROVE-IT study that pravastatin’s pleiotropic effects were found not to translate into a benefit equivalent to that of the more efficacious statin, atorvastatin. 39

The success of ezetimibe was its ability to safely and easily lower LDL-C in combination with statins to achieve treatment goals. For many patients, a lower-dose statin and ezetimibe together provide a well-tolerated and efficacious approach to treating hyperlipidemia. The fallout from the ENHANCE trial is that many patients who were well treated or who could be better treated with ezetimibe in combination with a statin will not receive the best tolerated regimen. In fact, preliminary prescription data after the release of the ENHANCE study support our worse fear, ie, that patients at high risk will receive less aggressive LDL-C reduction. Since the ENHANCE data were released, more than 300,000 patients have stopped taking either ezetimibe/simvastatin or ezetimibe, and nearly all have continued on generic simvastatin or on a dose of statin with less overall efficacy.

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