Immunomodulatory effect of different statin regimens on regulatory T-cells in patients with acute coronary syndrome: a systematic review and network meta-analysis of randomized clinical trials

Abstract Aims We conducted a network meta-analysis (NMA) to determine the effects of low-dose (20 mg/day or less) conventional statin therapy (CST) and high-dose (40 mg/day or more) intensive statin therapy (IST) on the frequency of Tregs and their associated cytokines (IFN-γ, IL-10, TGF-β) compared with control. Methods and results PubMed, Cochrane Library, and EMBASE databases were searched for randomized clinical trials (RCTs) to identify relevant articles published until June 2021. We pooled data extracted from the included studies using the standardized mean difference (SMD). A random-effects model was used to conduct this NMA. Heterogeneity was evaluated using Cochran's Q test and the I2 test. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was used to assess the quality of the study. Data analysis was conducted using R software. A total of 505 patients were enrolled in the five RCTs. NMA indicated a significant increase in Treg frequency in the CST group compared with the control group (SMD 1.77; 95% CI: 0.77–2.76; P = 0.0005) and a larger increase in the Treg frequency associated with the IST group compared with the control group (SMD 2.12; 95% CI: 1.15–3.10; P-value < 0.0001). However, there was significant heterogeneity and inconsistency among the included studies [τ2 = 0.6096; τ = 0.7808; I2 = 91.2% (80.5%; 96.0%)]. When compared with control, both CST and IST increased the levels of secreted IL-10 (SMD 2.69; 95% CI: 2.07–3.31; P-value < 0.0001 and SMD 2.14; 95% CI: 1.76–2.52; P-value < 0.0001). Compared with the control group, CST was associated with increased levels of TGF-β (SMD 3.83; 95% CI: 0.63–7.0; P-value = 0.0189); this association was not seen in the IST group. IFN-γ levels decreased significantly in both the IST and CST groups (SMD −1.52; 95% CI: −1.94–1.10; P-value < 0.0001 and SMD −2.34; 95% CI: −2.73–1.95; P-value < 0.0001, respectively). Conclusion The findings of our study indicated that both high- and low-dose statin groups increased Treg frequency compared with the control group. IST demonstrated greater benefits than CST. Furthermore, statin therapy increased IL-10 and TGF-β levels and decreased IFN-γ levels. Overall, these results have significant implications for patients with ACS who would benefit from Treg-induced immunomodulatory balance.