The End of Zetia?

We received news that the outcome study of ezetimibe or Zetia ,which is being performed under the name IMPROVE-IT, is slated to end in 2013.  Data should then be available by the fall of 2014.  Zetia’s patent expires in October 2016.  Zetia earned Schering-Plough 1.9 billion dollars in 2006, and they split this money with Merck.

Let me put this in prospective.  Two years before a multi-billion dollar drug undergoes patent release to generic, we will finally identify that the drug has some value beyond the lowering of a number.  This is truly amazing when you think about it. 

As I have blogged before in December 2009, this drug was approved on the basis of just the lowering of a chemical number and not that it reduces hard clinical endpoints.  That is what this study is to determine.  No one really cares if your LDL cholesterol number is lower just that fewer people die.  Let me again point out that the reduction number does not need to be large just statistically significant.

There unfortunately are significant differences in that number and its meaning.  Several blogs ago I discussed the new indication for Crestor.   In the final analysis you have to treat 1000 patients to prevent two deaths using Crestor under its new indication.  The number is significant statistically but is this indication really worth it to patients or just the company?

The issue was further clouded by the “lowering of the bar.”  As Dr. Califf pointed out, (Note:  I know Dr. Califf and he is one of the finest researchers in cardiology today) “because this study is done on a background of simvastatin the incremental absolute reduction in LDL is expected to be modest and as a result the anticipated absolute reduction in event rates will be modest also,” Am Heart J 2010. DOI: 10.1016

As pointed out in my previous blogs, the ARBITER 6-HALTS study findings were more valuable then these findings will be.

This goes back to the science of LDL cholesterol.  It is clear that patients who have peripheral vascular disease, stroke or coronary artery disease should be on maximally tolerated statin doses for the largest effect.  This goes for people who have reasonable levels of LDL reduction on small doses of drug because it is felt that some of these effects are “pleiotropic” or to put it another way “magical” and is not fully measurable.  These include the decrease of the “inflammation” of the LDL.

We know at least that Zetia is not causing harm because the study was not stopped by the monitoring safety board at half way in the study.  Whether it does any good and whether we can afford to pay for it as a society will be left to an answer probably at the American Heart meeting in November 2014.  Stay tuned…

Tags: Cholesterol, Coronary artery disease, IMPROVE-IT, peripheral vascular disease, Stroke, Zetia
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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
Posted in Carotid Disease, Cholesterol, Myocardial Infarction | No Comments »

The Ins and Outs of Clinical Research Studies

The American Heart Association meeting took place in Orlando this year and provided additional insight into the treatment of heart disease. One study in particular was eagerly awaited. This was the Arbiter6-Halts study. Study results are embargoed before presentation or publication. What this means is that no results can be discussed or presented in any format until its release time. This is in spite of many people knowing the results. The only time this is not done is if something is of great importance to public health. Then it is rushed to print on line. The web has made this vastly easier but all the more difficult in that information often “escapes” early.

In Arbiter’s case, the study compared niacin — a drug that I have blogged about several times in the past.  It is a very useful drug but one that is very difficult to take secondary to side effects. As I have also blogged, we are presently involved in an early phase study working on a compound that acts like niacin without the side effects.

Niacin was being compared to Zetia, or as it is known generically, ezetimibe. I have not spoken much about this drug because of my own bias about it. It is, however, widely used and has undergone several evaluations; most have been negative as far as its use.

When this study was stopped early this past summer, Wall Street immediately began to dump the stock of the company that manufactures it. This was compounded by the chairman of the company having to have a conference call and providing negative earnings guidance for the company. This was all before the data was presented and individuals had an opportunity to review it. Just another example of how intertwined everything we do is.

Also involved in this issue is the difference between the old and new FDA approval process. In the past, as in Zetia’s case, drugs were approved because they lowered cholesterol. Now the drug must lower cholesterol and provide a clinical benefit. This is a high hurdle but a distinction that is critical. Why take a drug unless you get a benefit for it? When Zetia was approved it did not have outcome data. This is why these studies are so important.

Next…what is Zetia?

Tags: Arbiter6-Halts study, Ezetimibe, Niacin, Zetia
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