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Combination of
Ezetimibe via Niemann-Pick C1-Like 1 protein
Simvastatin Statin HMG-CoA reductase inhibitor
Clinical data
Legal status
  • Prescription only
Routes Oral
CAS number 444313-53-5 YesY
ATC code C10BA02
ChemSpider 21106308 YesY
 YesY (what is this?)  (verify)

Ezetimibe/simvastatin /ɛˈzɛtɨmɪb ˌsɪmvəˈstætɨn/ 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.

Simvastatin is an HMG-CoA reductase inhibitor or statin. It works by blocking an enzyme that is necessary for the body to make cholesterol.

Even though ezetimibe decreases cholesterol levels, as of 2009 it has not been found to lead to improvement in real world outcomes.[1] The combination of simvastatin and ezetimibe has not been found to be any better than simvastatin alone. A panel of experts thus concluded in 2008 that it should "only be used as a last resort".[2]


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.[3] It is thought that the treatment of high cholestrol from both sources is likely to result in lower cholesterol levels,[3] 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.[4]

Clinical trials[edit]

ENHANCE trial data[edit]

The two-year ENHANCE Study, released by the manufacturer as an abstract,[5] 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.[6] Data from studies specifically designed to answer this question are expected within the next few years.

Subsequent debate and enquiries[edit]

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.[7]

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.[6]

The results of the ENHANCE study have been long anticipated. These results were presented in full at the American College of Cardiology meeting on 30 March 2008. The House Committee on Energy and Commerce has started an inquiry into the delayed disclosure of the study data;[8] In addition there is an ongoing investigation into Carrie Smith Cox, Schering-Plough’s president, who sold 900,000 shares of company stock in April and May 2007 worth an estimated $28 million. This massive sell off comes after the ENHANCE trial was complete.[9]

Finally there is an inquiry into the popular Vytorin brand, direct-to-consumer (DTC) ads. The companies continued spending at least $155 million a year on TV ads that heralded Vytorin’s supposed superiority over statins alone, while withholding the ENHANCE results.[10]

IMPROVE-IT trial[edit]

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.[11]

Results of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial[12] showed a potential increase in cancer in association with the use of these drugs together.[13] The actual significance has yet to be determined.

Advertising campaign[edit]

In the United States, the Vytorin brand has become rather well known for its 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.[14] This point is a departure from the commonly held belief that high cholestrol only comes from the food that you eat.[15] In each commercial, the person is dressed, 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, 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

Side effects[edit]



  1. ^ "NEJM -- Extended-Release Niacin or Ezetimibe and Carotid Intima-Media Thickness". 
  2. ^ Mitka M (May 2008). "Cholesterol drug controversy continues". JAMA 299 (19): 2266. doi:10.1001/jama.299.19.2266. PMID 18492963. 
  3. ^ a b Physicians Agree That Treating Two Sources Of Cholesterol Likely To Achieve Greater LDL-Cholesterol Reductions
  4. ^ VYTORIN could lower bad cholesterol (LDL-C) more than Lipitor, New Trial Shows
  5. ^ Schering-Plough - News and Media - News Releases
  6. ^ a b Park, Alice (2008-01-15). "Is Vytorin a Failure?". Time. Retrieved 2010-05-02. 
  7. ^ Vytorin Results Disappointing, Experts Say Don't Panic
  8. ^ 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 |title= (help)[dead link]
  9. ^ Pharmalot » Congress To Probe Vytorin Insider Stock Sales
  10. ^ Vytorin Ads Scrutinized by Lawmakers
  11. ^ IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome:Vytorin (Ezetimibe/Simvastatin) vs Simvastatin (Study P04103)
  12. ^ (ClinicalTrials.gov number, NCT00092677 [ClinicalTrials.gov])
  13. ^ 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. 
  14. ^ Chart: Most-Recalled New Prescription Drug Ads 2006-07 TV Season - TVWeek - News
  15. ^ Most Americans do not know that high cholesterol comes from two sources

External links[edit]