Treatment with ezetimibe increases levels of the atherogenic small, dense low-density lipoprotein (LDL) cholesterol subfractions, a small randomized trial in healthy men indicates.

Simvastatin reduced one of these subfractions, but ezetimibe given in combination offset the beneficial effect of the statin, say Ioanna Gouni-Berthold (University of Cologne, Germany) and colleagues.

The researchers believe their findings may help to explain why ezetimibe failed to augment the effect of simvastatin on carotid intima-media thickness in the ENHANCE trial, despite boosting its LDL cholesterol-lowering effect.

The current study included 72 healthy normocholesterolemic men, who were randomly assigned to receive ezetimibe 10 mg/day, simvastatin 40 mg/day, or the combination for 14 days.

LDL cholesterol fell by 22.1% with ezetimibe, 40.7% with simvastatin, and 59.6% with combination therapy.

During therapy, men taking ezetimibe only had 14.2% and 16.7% increases in the small, dense LDL subfractions LDL-IVA and LDL-IVB, respectively. Those taking simvastatin only had a small increase in the LDL-IVA subfraction, but a 16.7% reduction in the LDL-IVB subfraction.

However, this benefit was abolished by the addition of ezetimibe: men taking combination therapy had respective 28.5% and 14.3% increases in the IVA and IVB subfractions.

Both drugs reduced levels of the largest, most buoyant (ie, least atherogenic) LDL sufraction, but ezetimibe did so markedly more than simvastatin, at 13.9% versus 4.6%.

Gouni-Berthold et al found that the subfraction changes in men taking ezetimibe only were moderated by baseline LDL cholesterol levels, such that the higher the baseline levels, the greater the increase in small, dense LDL particles.

“Considering that the population of the current study was normocholesterolemic and that ezetimibe is prescribed to patients with much higher LDL cholesterol levels, it can be postulated that the pro-atherogenic effects of ezetimibe would be even more pronounced in the latter population,” they comment in the European Heart Journal.

“Although it could be argued that ezetimibe is usually prescribed along with a statin, a group in which such an association was not observed, it should be pointed out that ezetimibe monotherapy is a widely used alternative for the treatment of hypercholesterolemia in patients with statin intolerance.”