Ezetimibe Proves Clinical Benefit on Top of Statin Therapy

CHICAGO, IL—Addition of the cholesterol-lowering agent ezetimibe to statin therapy decreases cardiovascular events compared with what can be achieved with a statin alone, according to results of the long-awaited IMPROVE-IT study presented November 17, 2014, at the American Heart Association Scientific Sessions. Moreover, the combination therapy substantially reduces LDL cholesterol levels. 

“We now have solid evidence that lower is good, and even lower can be even better,” said Christopher P. Cannon, MD, of Brigham and Women’s Hospital (Boston, MA), who presented the findings. In fact, the decline in LDL was directly proportional to the improvement in outcomes, he added.

For the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), investigators enrolled 18,144 moderate-to-high-risk patients stabilized after a recent ACS event who had LDL levels below 125 mg/dL (or 100 mg/dL if on chronic statins). Patients were randomized to 40 mg of simvastatin with or without 10 mg of ezetimibe. If consecutive follow-up measures of LDL were greater than 79 mg/dL, the simvastatin dose was increased to 80 mg. 

Average age was 64 years, three-quarters of the cohort were men, and slightly more than one-quarter had diabetes. About one-third of both arms had prior lipid therapy, and the baseline LDL was 95 mg/dL.

Complementary Mechanisms 

In the drug combination Vytorin (Merck), simvastatin inhibits cholesterol synthesis in the liver, while ezetimibe inhibits its absorption in the intestine, producing an added 20% reduction in LDL.

Over 8 years, median LDL was 53.7 mg/dL in the simvastatin/ezetimibe group vs 69.5 mg/dL in the simvastatin alone group, a difference that appeared after 1 year and was accompanied by declines in triglycerides. 

At 7-year follow-up, intention-to-treat analysis showed a lower rate of the primary endpoint (composite of cardiovascular death, nonfatal MI, rehospitalization for unstable angina, revascularization beyond 30 days, or stroke) in the simvastatin/ezetimibe group than in the simvastatin group. The drug combination was also favored for several secondary endpoints (table 1).

Table 1. Outcomes at 7 Years

The number needed to treat to prevent 1 primary endpoint event over the study period was 50.

In particular, the combination therapy reduced MI by 13%, stroke by 14%, and ischemic stroke by 21%. There was a trend toward lower rates of revascularization. No difference was seen in mortality. 

Subgroup analyses based on sex, an age cutoff of 65 years, diabetes status, prior lipid-lowering therapy, and LDL level above or below the cutoff of 95 mg/dL all favored simvastatin/ezetimibe. The only interaction was found with diabetes, the absence of which tempered the benefit of simvastatin/ezetimibe (P for interaction = .023).

Importantly, since earlier trials had raised safety signals about the combination therapy, especially with regard to cancer, there were no differences between the groups in rates of side effects including liver enzymes, gallbladder events, rhabdomyolysis, myopathy, and cancer over the course of the study. 

More Options

Commenting on the trial, Neil J. Stone, MD, of Northwestern University Feinberg School of Medicine (Chicago, IL), said it “reaffirms the central role of intensive LDL reduction in the prevention of recurrent cardiac events.” The results expand the options for additional proven lipid-lowering therapies, he commented, adding that “perhaps we have not yet established a lower boundary of the benefits of lowering LDL [cholesterol] in this highest-risk group—if we can do it safely.” 

As to whether these results might prompt a change in the ACC/AHA cholesterol guidelines, Dr. Stone noted that the recommendations already allow clinicians to consider adding a nonstatin cholesterol-lowering therapy to the treatment of high-risk patients who have an inadequate response to statins and or cannot tolerate the recommended intensity of therapy—provided randomized clinical trials have shown that the benefits outweigh the potential for adverse effects. Until now, that not been the case, he pointed out, adding that there is still strong evidence for high-intensity statin therapy as secondary prevention.

Robert Harrington, MD, of the Stanford University School of Medicine (Stanford, CA), noted that the cholesterol guidelines committee does not consider new data until they are “in the peer review realm.” When they are published, it will be appropriate to consider a change, he added. 

Dr. Stone said the safety reassurance provided by this long, large-scale trial is crucial. But, he cautioned, the trial does not address the use of ezetimibe for primary prevention in lower-risk patients. If the findings were extrapolated to a lower-risk population, the absolute benefit would be lower, he noted.

“This is not a signal that everyone should be on this therapy,” Dr. Stone concluded. The trial “simply speaks to the biology of ‘lower is better’ for effective therapy.”


Cannon CP. IMPROVE-IT trial: a comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes after acute coronary syndromes. Presented at: American Heart Association Scientific Sessions; November 17, 2014; Chicago, IL.

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  • The IMROVE-IT trial was supported by a grant from Merck.
  • Dr. Cannon reports receiving research grants and honoraria from multiple pharmaceutical companies, including Merck.
  • Dr. Stone reports no relevant conflicts of interest.