The effect of ezetimibe, administered alone or in combination with simvastatin, on lymphocyte cytokine release in patients with elevated cholesterol levels

J Intern Med. 2012 Jan;271(1):32-42. doi: 10.1111/j.1365-2796.2011.02394.x. Epub 2011 May 30.


Objective: Studies assessing the extra-lipid effects of ezetimibe have provided contrasting results. In the present study, we compared the effects of ezetimibe and simvastatin, administered alone or in combination, on the secretory function of human lymphocytes, systemic inflammation and endothelial function in subjects with elevated cholesterol levels.

Methods: A prospective study involving a group of 178 ambulatory patients with isolated hypercholesterolaemia who were randomly assigned in a double-blind fashion to 90days of treatment with ezetimibe (10mg), simvastatin (40mg), ezetimibe (10mg) plus simvastatin (4mg) or placebo. A total of 170 patients completed the study.

Main outcome measures: Lymphocyte cytokine release and plasma levels of high-sensitivity C-reactive protein (hsCRP) and intercellular adhesion molecule 1 (ICAM-1).

Results: Although both drugs reduced lymphocyte release of tumour necrosis factor-α, interferon-γ and interleukin-2 in a lipid-independent manner, only the effect of simvastatin was statistically significant (P<0.001). This lymphocyte-suppressing effect, which was accompanied by a decrease in plasma levels of hsCRP and ICAM-1 (P<0.001), was strongest in patients receiving both simvastatin and ezetimibe. There were no differences in lymphocyte-suppressing, systemic anti-inflammatory and endothelial protective effects of simvastatin between insulin-resistant and insulin-sensitive subjects, whereas the effects of ezetimibe and the combined treatment were greater in the former group of patients (P<0.01 and P<0.001, respectively).

Conclusions: The results of this study indicate that simvastatin is superior to ezetimibe in producing lymphocyte-suppressing, systemic anti-inflammatory and endothelial protective effects in patients with elevated cholesterol levels. Hypercholesterolaemic patients with high cardiovascular risk may receive the greatest benefits from concomitant treatment with a statin and ezetimibe.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticholesteremic Agents / administration & dosage*
  • Azetidines / administration & dosage*
  • Cytokines / metabolism*
  • Double-Blind Method
  • Drug Therapy, Combination
  • Ezetimibe
  • Female
  • Humans
  • Hypercholesterolemia / complications
  • Hypercholesterolemia / drug therapy*
  • Hypercholesterolemia / immunology*
  • Inflammation / etiology
  • Inflammation / prevention & control
  • Lymphocytes / drug effects*
  • Lymphocytes / metabolism*
  • Male
  • Middle Aged
  • Prospective Studies
  • Simvastatin / administration & dosage*


  • Anticholesteremic Agents
  • Azetidines
  • Cytokines
  • Simvastatin
  • Ezetimibe