Drugs: From A(pproval) to Z(etia)

I was discussing the use of the drug Zetia before I was interrupted by the FDA so I will now return to that. Zetia is a novel compound that is used either with or without a statin. Zetia works on the lining of the small intestine to block the absorption of cholesterol from the intestines. It is not fully understood why all cholesterol in the body is transported into the intestines to then be reabsorbed into the circulation. It is this step that Zetia blocks and it is how cholesterol is lowered. The cholesterol synthesis pathway is “feedback,” i.e. if the level of cholesterol is lower than the body thinks it needs, the liver will produce more cholesterol. It is this step that the statin blocks so that the combination of a statin and Zetia is a very effective way to lower LDL cholesterol.

This is how Zetia got its approval. It dates back to 2006, when any drug was approved by the FDA if it simply lowered cholesterol. Now the FDA requires a proven clinical benefit before granting approval. Zetia has yet to prove that clinical benefit and that is where the controversy arises. In fact–in every study to date–although the combination of Zetia and statin lowers cholesterol, the endpoints for the study have not been met and Zetia always does worse.

My particular problem with the combination is that it is often used to lower the amount of statin used in individual patients. We have large amounts of data that indicate the higher the dose of statin one takes, the better the outcomes. LDL lowering is an easily measured end point for something we can not easily measure. We don’t care what the level of LDL really is; we want to obtain the lowering of death, myocardial infarction and unstable angina-which is what statins do. The higher the dose of statins, the more effect they have on decreasing the endpoints that truly matter.

Two studies have now used the endpoint of the increase in plaque buildup in the carotid arteries. ENHANCE reported in 2008 and now ARBITER-6 released this past month. Neither study involved clinical endpoints. They did not evaluate whether fewer strokes or myocardial infarctions occurred. They simply determined which group had a better imaging response. In both studies, Zetia failed. In ENHANCE against simvastatin alone and in ARBITER-6 niacin performed better than the combination.

Physicians are divided on how to use this drug. A panel of FDA experts declared that it should be used “as a last resort” to lower cholesterol. The real proof will have to wait until 2013. That is when the results from IMPROVE-IT will most likely be released at the American College of Cardiology meeting. This study started several years ago will randomize 18,000 patients and follow them for a minimum of two and one-half years. The primary end points are death and myocardial infarction. The study uses simvastatin vs. the combination of Zetia and simvastatin.

Your particular use of Zetia is defined by your needs and your doctor’s advice. This is the backdrop against which this drug is prescribed. As always you should discuss your medication use with your physicians.

Tags: FDA, Statin, Zetia

This entry was posted on Tuesday, December 8th, 2009 at 8:52 am and is filed under Carotid Disease, Cholesterol, Myocardial Infarction. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.