Ezetimibe (Vytorin) For Cholesterol

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Ezetimibe is a drug that lowers cholesterol levels. It has been FDA approved since 2002. However, the drug has been somewhat controversial since its introduction, and experts still argue about its appropriate place in the treatment of lipid disorders.

How Does Ezetimibe Work?

Ezetimibe works by blocking cholesterol absorption from the intestines.

Normally, the cholesterol absorbed from the intestines is carried by chylomicrons to the liver, where it is used for several important processes.

When the amount of absorbed cholesterol is reduced by ezetimibe, the liver has to get its supply of cholesterol by removing it from the lipoproteins circulating in the bloodstream. Thus, blood levels of cholesterol are reduced.

Generally, ezetimibe either by itself or in combination with a statin reduces the amount of LDL cholesterol in the blood by about 15%.

What Are The Side Effects?

In general, ezetimibe is well-tolerated. Nausea, diarrhea, and allergic reactions may occur. While myopathy (muscle side effects) has been reported with ezetimibe, similar to the myopathy seen with statins, the incidence of this side effect appears to be much lower than with statins. In fact, one indication for using ezetimibe is to add it to low-dose statins, in order to achieve the desired cholesterol reduction without the myopathy sometimes seen with high-dose statins.

What Is The Controversy With Ezetimibe?

When ezetimibe was first approved, it was heavily marketed as Vytorin, a combination of ezetimibe and simvastatin, and sales were brisk.

You may recall frequent commercials comparing your sweet, rotund Aunt Suzie to a big piece of strawberry shortcake a la mode. That was Vytorin. (Ezetimibe is also sold as a stand-alone drug under the name Zetia.)

It turns out that, while those commercials were running and while Merck was selling billions of dollars of Vytorin, publication was being (suspiciously, some said) delayed of a Merck-sponsored clinical trial called the ENHANCE study.

ENHANCE was aimed at proving that Vytorin improved atherosclerotic plaques more than simvastatin alone. When the results were finally released in 2008, it was learned that patients treated with Vytorin did slightly worse (not better) than those receiving simvastatin alone.

Because of these negative results (and the fact that many considered the delay in reporting those results to be at least unseemly), sales of ezetimibe tanked. And the commercials disappeared altogether.

Interest in ezetimibe has revived somewhat since 2014, when the results of the IMPROVE-IT trial were published. In this trial, patients with acute coronary syndrome (ACS) were randomized to receive either Vytorin or simvastatin alone. After 6 years, patients receiving Vytorin had modestly improved clinical outcomes (fewer readmissions for ACS, and less need for subsequent bypass surgery or stents), but there was no difference in survival.

A subgroup analysis of the IMPROVE-It trial suggested that virtually all the benefit seen in the Vytorin group could be accounted for by patients with diabetes.

In people without diabetes, no benefit from adding ezetimibe could be shown.

In December, 2015, an FDA advisory committee declined to expand the indications for ezetimibe based on the modest positive results of IMPROVE-IT.

When Should Ezetimibe Be Used?

The use of ezetimibe should be quite limited. Current guidelines (published in 2013) on cholesterol do not recommend treating to any particular target cholesterol level. Rather, they focus on deciding whether to use a statin drug or not. So “secondary” cholesterol-lowering drugs like ezetimibe have very little place under these guidelines.

Doctors sometimes prescribe ezetimibe and low-dose statins in people who should be on high-dose statins, but cannot tolerate the high dose.

Also, ezetimibe is sometimes used instead of statins in patients who simply cannot take statins at any dose.

Finally, on the basis of the IMPROVE-IT study, many cardiologists deem it reasonable to use ezetimibe plus a statin in diabetic patients who have had recent ACS (despite the FDA declining to make this a formal recommendation).

Aside from these few clinical situations, there is currently not much reason to take ezetimibe.


Kastelein JJ, Akdim F, Stroes ES et al.; ENHANCE Investigators: Simvastatin with or without ezetimibe in familial hypercholesterolemia. N. Engl. J. Med. 358, 1431–1443 (2008).

Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015; 372:2387.

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