Context: Ezetimibe and simvastatin are often used in combination to lower blood lipid levels. The consequences of this combination at the molecular level are unknown.
Objective: To examine their effects on the LDL receptor (LDLR) protein expression and on the LDLR and HMG-CoA reductase gene expression in peripheral blood mononuclear cells (PBMC).
Design, setting and participants: Prospective, randomized, parallel 3-group trial. Twenty-four healthy men (mean age 32±9 years) received a 14-day treatment with either ezetimibe (10 mg/day), or simvastatin (40 mg/day) or their combination. Blood was drawn before and after treatment.
Main outcome measures: LDLR protein expression, and LDLR and HMG-CoA reductase gene expression, lipid levels, non-cholesterol sterols and the ratio of precursor sterols over cholesterol concentrations, a valid marker of cholesterol synthesis and HMG-CoA reductase activity.
Results: LDL-C decreased by 22±10%, 41±12%, and 60±10% in the ezetimibe, simvastatin and combination groups, respectively (all P<0.0001). The HMG-CoA reductase gene expression increased significantly in the simvastatin (+33%; P=0.032) and combination groups (+36%; P=0.0056) and remained unchanged in the ezetimibe group (+14%; P=0.27). Similarly, the LDLR gene expression increased significantly in the simvastatin (+72%; P=0.024) and combination groups (+56%; P=0.0012), but not in the ezetimibe group (+14%; P=0.49). The LDLR protein expression, however, remained unchanged in all groups.
Conclusions: Unlike simvastatin, the lipid-lowering effects of ezetimibe do not involve an upregulation of the HMG-CoA reductase or LDLR gene expression. The simvastatin-induced upregulation of the LDLR gene expression did not lead to an increase in the LDLR protein. Further studies are necessary to fully clarify the posttranscriptional mechanisms regulating LDLR protein abundance.