Immunomodulatory_Roles_of_Statin/Ezetimibe

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[Title of corresponding article] 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 [Author list] Sang-Hyeon Ju1†, Thi Linh Nguyen2†, Joung Youl Lim1, Minchul Song1, Ji Min Kim3,4, Yea Eun Kang1,4, Hyon-Seung Yi1,2,4, Kyong Hye Joung3,4, Ju Hee Lee1,4, Hyun Jin Kim1,4, Bon Jeong Ku1,4* 1Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea 2Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Republic of Korea 3Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University Sejong Hospital, Sejong, Republic of Korea 4Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea. †; equal contribution for co-first author *; corresponding author [Abstract] Objectives Chronic low-grade inflammation has been 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. 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 into rosuvastatin (N=74) or rosuvastatin/ezetimibe group (N=75). Immunophenotype of peripheral blood mononuclear cells and metabolic profiles were analyzed using samples of baseline and post-12 weeks of medication. Results Fractions of CD8+CD57+ (senescent CD8+ T cells) and CD4+FoxP3+ (Tregs) 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, 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 by rosuvastatin/ezetimibe treatment. Our results demonstrate the immunomodulatory roles of ezetimibe in combination with statins, which are independent of improvements in lipid or HbA1c levels.

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