LDL Trumps CIMT

The agency announced yesterday that patients should not stop taking Vytorin (ezetimibe/simvastatin) or any other cholesterol-lowering medication on the sole basis of the ENHANCE trial results. The conclusion follows the FDA's review of the final trial report, in which the combo drug was no better than simvastatin alone for reducing carotid intima-media thickness (CIMT) at 2 years. However, the LDL cholesterol level dropped 56% with Vytorin and 39% with simvastatin alone—a statistically significant difference.

The FDA maintains that an elevated LDL cholesterol level is an important risk factor for cardiovascular disease and that lowering the LDL level reduces that risk. The FDA also speculated as to why a larger reduction of the LDL level with Vytorin was not associated with a significantly reduced CIMT in the ENHANCE trial*:

• Because the ENHANCE population had received prior lipid-altering or statin therapy, subjects demonstrated relatively normal CIMT values at baseline, which made it harder to demonstrate a CIMT difference with Vytorin therapy.
• The duration of the ENHANCE trial, 2 years, was too brief to demonstrate a difference in CIMT with therapy.
• Unknown effects of ezetimibe may negate the beneficial effects of LDL lowering on CIMT.

The FDA advises that the much larger, ongoing IMPROVE-IT study, which pits Vytorin against simvastatin alone and has a primary composite endpoint of cardiovascular events and stroke, should provide more definitive information about the clinical benefits of the drug. The trial, however, won't be completed until 2012.

* The FDA doesn't mention previously reported problems with the CIMT data in the ENHANCE trial, such as missing or biologically implausible data.

ENHANCE = Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia; IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL = low-density lipoprotein.