|Ezetimibe||via Niemann-Pick C1-Like 1 protein|
|Simvastatin||Statin HMG-CoA reductase inhibitor|
|CAS Registry Number|
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Ezetimibe/simvastatin / / is a drug combination used for the treatment of dyslipidemia. It is a combination of ezetimibe (known as Zetia in the United States and Ezetrol elsewhere) and the statin drug simvastatin (known as Zocor in the U.S.). The combination preparation is marketed by Merck & Co. under the trade names Vytorin and Inegy.
Ezetimibe reduces blood cholesterol by acting at the brush border of the small intestine and inhibiting the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver.
Even though ezetimibe decreases cholesterol levels, as of 2009 it has not been found to lead to improvement in real world outcomes. The combination of simvastatin and ezetimibe has not been found to be any better than simvastatin alone.
The combination of ezetimibe and simvastatin is the only product to treat both sources of cholesterol; absorption in the intestine of both biliary and dietary cholesterol, and production in the liver and peripheral tissues. It is thought that the treatment of high cholestrol from both sources is likely to result in lower cholesterol levels, particularly LDL cholesterol. In a clinical study, it was shown that the combination of ezetimibe and simvastatin was superior to atorvastatin in lowering LDL cholestrol.
ENHANCE trial data
The two-year ENHANCE Study, released by the manufacturer as an abstract, recently failed to provide evidence that ezetimibe/simvastatin was better than simvastatin (a generic medication) in terms of achieving a lower change from baseline in carotid intima-media thickness despite lower LDL levels in a population of patients with heterozygous familial hypercholesterolemia (a form of high cholesterol that affects less than 1% of patients). Clinical events such as heart attack and stroke were not measured as primary or secondary endpoints of the study making it impossible to determine Vytorin's effect on these events. Data from studies specifically designed to answer this question are expected within the next few years.
Subsequent debate and enquiries
The American College of Cardiology released a statement suggesting that "major clinical decisions not be made on the basis of the ENHANCE study alone", given the small and unique patient population, 720 patients in an Amsterdam hospital with heterozygous familial hypercholesterolemia.
Merck and Schering Plough have reported that they have three trials underway to focus on outcomes, measuring the drug's effect on heart attacks and strokes in patients.
These results were presented in full at the American College of Cardiology meeting on 30 March 2008, a full two years after the last patient was enrolled in the study. The House Committee on Energy and Commerce conducted an inquiry into the delayed disclosure of the study data. Advertisements supporting the superiority of ezetimibe plus simvastatin to simvastatin alone continued to run after Schering management presumably know of the negative results of the trial.
Vytorin is currently undergoing another randomized control trial (IMPROVE-IT). This trial will measure the effects of Vytorin vs. simvastatin alone in determining primary outcomes of cardiovascular and cerebrovascular events in 18,000 patients who have been hospitalized for an acute coronary syndrome. The patients will be followed for a minimum of 2.5 years. The trial is expected to end in September 2014.
Results of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial showed a potential increase in cancer in association with the use of these drugs together. The actual significance has yet to be determined.
In the United States, Vytorin featured a television advertising campaign showing a series of split-screen images of a person and a food item to make the point that cholesterol comes from two sources and can be absorbed from food or manufactured by the body, and that heredity plays a role in the latter. This point is a departure from the commonly held belief that high cholestrol only comes from the food that you eat. In each commercial, the person's features or clothing and the food plated to emphasize the resemblance between the person and the food. For example, in one advertisement a woman wearing a yellow shirt and a pin is juxtaposed with a similarly colored piece of pie; despite being praised for their clarity[by whom?], the ads have been noted as a prominent example of direct marketing to counteract known shortcomings of a product.
- Acute liver disease
- Pregnancy and breast feeding
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- "NEJM -- Extended-Release Niacin or Ezetimibe and Carotid Intima-Media Thickness".
- Physicians Agree That Treating Two Sources Of Cholesterol Likely To Achieve Greater LDL-Cholesterol Reductions
- VYTORIN could lower bad cholesterol (LDL-C) more than Lipitor, New Trial Shows
- Schering-Plough - News and Media - News Releases
- Park, Alice (2008-01-15). "Is Vytorin a Failure?". Time. Retrieved 2010-05-02.
- Vytorin Results Disappointing, Experts Say Don't Panic
- "The Vytorin Letters - Forbes".
- http://web.archive.org/web/20080120192442/http://www.forbes.com/feeds/ap/2007/12/12/ap4433892.html. Archived from the original on 2008-02-20. Missing or empty
- IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome:Vytorin (Ezetimibe/Simvastatin) vs Simvastatin (Study P04103)
- (ClinicalTrials.gov number, NCT00092677 [ClinicalTrials.gov])
- Drazen, Jeffrey M.; d'Agostino, Ralph B.; Ware, James H.; Morrissey, Stephen; Curfman, Gregory D. (2008). "Ezetimibe and Cancer — an Uncertain Association". New England Journal of Medicine 359 (13): 1398–9. doi:10.1056/NEJMe0807200. PMID 18765434.
- Chart: Most-Recalled New Prescription Drug Ads 2006-07 TV Season - TVWeek - News
- Most Americans do not know that high cholesterol comes from two sources
- Vytorin's official website
- Vytorin Information Sheet
- U.S. National Library of Medicine: Drug Information Portal - Ezetimibe/simvastatin