FDA review backs ezetimibe and simvastatin combination

After a year-long review of data from the ENHANCE trial that showed no significant difference in the changes in carotid artery thickness between patients treated with ezetimibe and simvastatin, vs. simvastatin alone, the Food and Drug Administration has concluded that patients should not stop taking ezetimibe/simvastatin or any cholesterol-lowering medications.

This recommendation largely reflects the results of ENHANCE (Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia), showing significant reductions in LDL cholesterol levels of patients who took ezetimibe, compared with those who took simvastatin alone, the FDA said.

The FDA’s conclusion supports the manufacturers' assertion that ezetimibe/simvastatin is effective, but other questions about the cholesterol-lowering therapy were not addressed in the agency’s updated safety review.

In the randomized, placebo-controlled SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study the therapy did not reduce major cardiovascular events and was linked to increased cancer deaths among asymptomatic patients with aortic stenosis. An immediate independent analysis of data on 20,000 patients treated so far in two other ongoing trials, SHARP (the Study of Heart and Renal Protection) and IMPROVE-IT (the Improved Reduction of Outcomes Efficacy International Trial), showed no increased cancer risk, but doubts have remained.

The FDA said that IMPROVE-IT scheduled to be completed in 2012, should address questions about cardiovascular events. About the FDA noted that in ENHANCE, ezetimibe/simvastatin reduced LDL, cholesterol by 56 percent vs. a 39 percent reduction with simvastatin.

“The results from ENHANCE do not change FDA’s position that an elevated LDL cholesterol is a risk factor for cardiovascular disease and that lowering LDL cholesterol reduces the risk for cardiovascular disease,” the agency said.

Explanations as to why the larger decrease in cholesterol didn’t lead to a greater improvement in carotid artery intimal medial thickness (cIMT) may include that the two-year study was too short and that “there may be unknown properties of ezetimibe that may negate the beneficial effects of LDL lowering on cIMT,” the FDA said.

The ezetimibe/simvastatin combination has been the subject of investigations by at least 35 state attorney generals and the US Department of Justice, focusing on the product.