Does Zetia® Work?

Zetia® (ezetimibe) has again become a useful add-on therapy to statins after being in a kind of limbo from contradictory studies.

Clinical Trials

The 2008 ENHANCE Trial sowed doubt about whether Zetia (ezetimibe) when added to Zocor (simvastatin), can prevent the bad outcomes associated with high cholesterol. Since that time the medical community was anxious for the results of the IMPROVE-IT Study to tell us whether Zetia can benefit patients. (The combination of Zetia and Zocor is marketed as Vytorin).

The results of IMPROVE-IT were presented in November 2014. In this study, over 18,000 patients with a recent acute coronary syndrome (ACS) took Zocor (simvastatin) to which either Zetia or placebo were added. The investigators waited 7 years until there were enough cardiovascular deaths, heart attacks, hospitalizations for angina, coronary bypasses, stents and strokes to analyze the data and produce meaningful results. Adding all of these different adverse outcomes together allowed researchers to compare the Zetia and placebo groups.


It turned out that Zetia lowered LDL (bad) cholesterol to 53.2 vs 69.9 for placebo. And fewer adverse outcomes occurred in the Zetia group (32.7%) vs 34.7% in the placebo group, a 2% difference. Put another way, one had to treat 50 patients with Zetia (on top of Zocor) to prevent one adverse event over 7 years. Most of the benefit was due to fewer heart attacks and strokes.

Compared to the much larger proven benefit of statin drugs alone, adding Zetia to Zocor produced a pretty modest improvement. Only the very large size of the patient group and the long duration of the study made even this modest difference statistically significant and not likely due to chance.

Zetia is the first non-statin drug to show any benefit when added to a statin. But IMPROVE-IT leaves open the question of whether additional lowering of LDL cholesterol with Zetia yields better, worse or the same benefit as switching from Zocor to a more potent statin, such as Lipitor (atorvastatin) or Crestor (rosuvastatin).

Certainly there is a plausible role for Zetia in lowering LDL in patients who have trouble tolerating high dose or high potency statins. But there are many well done trials showing the benefit of high potency statins, and just one study now showing a modest effect of adding Zetia to Zocor.  Our approach will be to rely on the stronger statins if they can do the job alone. If they are not enough, Zetia may be a logical add on.

With even newer and more potent drugs like the expensive injectable Praluent® and Repatha® , we have more evidence that very very low LDL improves prognosis in patients with cholesterol deposits in their arteries or patients with genetically caused very high cholesterol levels. More on that later.