Distinct effects of rosuvastatin and rosuvastatin/ezetimibe on senescence markers of CD8+ T cells in patients with type 2 diabetes mellitus: a randomized controlled trial

Front Endocrinol (Lausanne). 2024 Mar 22:15:1336357. doi: 10.3389/fendo.2024.1336357. eCollection 2024.

Abstract

Objectives: Chronic low-grade inflammation is widely recognized as a pathophysiological defect contributing to β-cell failure in type 2 diabetes mellitus (T2DM). Statin therapy is known to ameliorate CD8+ T cell senescence, a mediator of chronic inflammation. However, the additional immunomodulatory roles of ezetimibe are not fully understood. Therefore, we investigated the effect of statin or statin/ezetimibe combination treatment on T cell senescence markers.

Methods: In this two-group parallel and randomized controlled trial, we enrolled 149 patients with T2DM whose low-density lipoprotein cholesterol (LDL-C) was 100 mg/dL or higher. Patients were randomly assigned to either the rosuvastatin group (N=74) or the rosuvastatin/ezetimibe group (N=75). The immunophenotype of peripheral blood mononuclear cells and metabolic profiles were analyzed using samples from baseline and post-12 weeks of medication.

Results: The fractions of CD8+CD57+ (senescent CD8+ T cells) and CD4+FoxP3+ (Treg) significantly decreased after intervention in the rosuvastatin/ezetimibe group (-4.5 ± 14.1% and -1.2 ± 2.3%, respectively), while these fractions showed minimal change in the rosuvastatin group (2.8 ± 9.4% and 1.4 ± 1.5%, respectively). The degree of LDL-C reduction was correlated with an improvement in HbA1c (R=0.193, p=0.021). Changes in the CD8+CD57+ fraction positively correlated with patient age (R=0.538, p=0.026). Notably, the fraction change in senescent CD8+ T cells showed no significant relationship with changes in either HbA1c (p=0.314) or LDL-C (p=0.592). Finally, the ratio of naïve to memory CD8+ T cells increased in the rosuvastatin/ezetimibe group (p=0.011), but not in the rosuvastatin group (p=0.339).

Conclusions: We observed a reduction in senescent CD8+ T cells and an increase in the ratio of naive to memory CD8+ T cells with rosuvastatin/ezetimibe treatment. Our results demonstrate the immunomodulatory roles of ezetimibe in combination with statins, independent of improvements in lipid or HbA1c levels.

Keywords: CD8-Positive T-Lymphocytes; Hydroxymethylglutaryl-CoA reductase inhibitors; Type 2; cellular senescence; diabetes mellitus; ezetimibe.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Anticholesteremic Agents* / therapeutic use
  • Azetidines* / therapeutic use
  • Cholesterol, LDL
  • Diabetes Mellitus, Type 2* / drug therapy
  • Drug Therapy, Combination
  • Ezetimibe / therapeutic use
  • Fluorobenzenes / therapeutic use
  • Glycated Hemoglobin
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors* / therapeutic use
  • Hypercholesterolemia* / drug therapy
  • Inflammation / drug therapy
  • Leukocytes, Mononuclear
  • Pyrimidines
  • Rosuvastatin Calcium / therapeutic use
  • Sulfonamides / therapeutic use
  • T-Lymphocytes
  • Treatment Outcome

Substances

  • Rosuvastatin Calcium
  • Ezetimibe
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Cholesterol, LDL
  • Anticholesteremic Agents
  • Glycated Hemoglobin
  • Azetidines
  • Fluorobenzenes
  • Pyrimidines
  • Sulfonamides

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by Yuhan Corporation (IIT-009). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.