Diabetologie und Stoffwechsel 2006; 1 - A53
DOI: 10.1055/s-2006-943778

Effects of ezetimibe on LDL receptor- and HMG-CoA reductase-gene expression, on LDL receptor protein expression and on HMG-CoA reductase activity in mononuclear blood cells of healthy men – A randomized trial

I Berthold 1, Y Ko 2, S Stier 2, E Giannakidou 1, H Gylling 3, J Plat 4, HK Berthold 5, W Krone 1
  • 1Medizinische Klinik II der Universität zu Köln, Köln, Germany
  • 2Medizinische Poliklinik der Universität Bonn, Bonn, Germany
  • 3Department of Clinical Nutrition, University of Kuopio, Kuopio, Finland
  • 4Department of Human Biology, Maastricht University, Maastricht, Netherlands
  • 5Arzneimittelkommission der deutschen Ärzteschaft, Berlin, Germany

Purpose of the study: Achieving target LDL-cholesterol (LDL-C) levels is of utmost importance, especially in patients with diabetes mellitus. The combination of simvastatin and the cholesterol absorption inhibitor ezetimibe is widely used to attain this goal. Purpose of the present study was to examine the effects of these agents and their combination on LDL-receptor- (LDLR) and HMG-CoA reductase-gene expression, on the LDLR protein expression and on the HMG-CoA reductase activity in peripheral blood mononuclear cells (PBMC).

Methods: The study is a prospective, randomized, parallel 3-group trial. Three groups of 24 men each received a 14-day treatment with ezetimibe (10mg/day), simvastatin (40mg/day) or their combination. Blood drawing was performed on days 1 and 14. LDL-receptor protein expression was measured by flow cytometry, LDLR and HMG-CoA gene expression using real-time PCR. Plasma markers of cholesterol synthesis (lathosterol, desmosterol, cholestenol) and absorption (cholestanol, sitosterol, campesterol) were determined by GC/MS.

Results: LDL-C decreased by 22±10%, 41±12%, and 60±10% in the ezetimibe, simvastatin and combination groups, respectively. Cholesterol absorption was decreased in all three treatment groups. Cholesterol synthesis remained unchanged in the combination group, was decreased in the simvastatin group and showed a compensatory increase in the ezetimibe group which, however, did not reach significance. The HMG-CoA reductase and the LDLR gene expression increased significantly in the simvastatin and combination groups and remained unchanged in the ezetimibe group. The LDLR protein expression remained unchanged in all three groups.

Conclusions: Unlike simvastatin, the lipid-lowering effects of ezezimibe do not involve upregulation of the HMG-CoA reductase or of the LDLR gene expression. Interestingly, the simvastatin-induced upregulation of the LDLR gene expression does not lead to an increase in the LDLR protein, suggesting the presence of posttranslational mechanisms that independently regulate LDLR protein abundance.