Ezitimibe alone and in combination lowers concentrations of small, dense low density lipoproteins in type 2 diabetes mellitus

Aims: The effectiveness of the cholesterol absorption inhibitor ezetimibe on LDL subfraction and finally on atherosclerotic risk profile is controversially discussed mostly due to inappropriate study population, laboratory methods and data interpretation. Therefore, concentrations of atherogenic small, dense LDL (sdLDL) were determined by ultracentrifugation in patients with type 2 diabetes mellitus (T2DM) with an elevated cardiovascular risk profile Methods and Results: Multicenter, randomized, double-blind study investigating the 6-week effect of ezitimibe 10 mg (E), simvastatin 20 mg (S) and combination of ezitimibe/simvastatin 10/20 mg (S/E) on concentrations of sdLDL separated from fresh plasma by endpoint gradient ultracentrifugation in patients with T2DM (Eudra-CT 2006-005906-30). Fifty-six patients were screened for sdLDL, 41 were randomized, and 40 patients (12 E; 14 S and 14 SE) completed the study. Total and LDL cholesterol were reduced by 14% (p = 0.004) and 15% (p = 0.006) with E, 22% (p < 0.001) and 32% (p < 0.001) with S, and 32% (p < 0.001) and 44% (p < 0.001) with S/E, respectively. However, E almost exclusively reduced concentrations of sdLDL by 20% (p = 0.043) whereas S and S/E reduced sdLDL by 24% (p = 0.020) and 33% (p = 0.003), and non-sdLDL by 28% (p = 0.004) and 42% (p < 0.001), respectively. Conclusions: Ezetimibe alone and in combination reduced concentrations of atherogenic sdLDL. Thus, a potentially proatherogenic effect of ezetimibe by increasing sdLDL could not be confirmed but was rather disproved.