Effect of Combination Therapy with Ezetimibe and Statins versus Statin Monotherapy on Carotid Intima-Media Thickness: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

Background and Objectives: Lipid-lowering agents such as ezetimibe are recommended in uncontrolled hyperlipidemia for primary and secondary prevention of cardiovascular disease. Carotid intima-media thickness (CIMT) is a surrogate marker of atherosclerosis and a predictor of cardiovascular and cerebral events. The effects of ezetimibe on CIMT have been inconsistently reported. The aim of this meta-analysis is to compare the effects of ezetimibe/statin and statin alone therapies on CIMT reduction. Materials and Methods: The PubMed, Embase, and Cochrane library databases were searched for randomized controlled trials (RCTs) published prior to 26 January 2023 with the MeSH keywords 'Ezetimibe' and 'Carotid Intima-Media Thickness'. The results were presented as standard mean difference (SMD) with 95% confidence intervals using the random-effect model method, and heterogeneity was assessed. Subgroup, meta-regression, and sensitivity analyses were conducted. Results: Five RCTs with 642 participants were included. CIMT reduction was not significantly different between the ezetimibe/statin and statin alone groups. However, in subgroup analyses, CIMT in the ezetimibe/statin group was significantly reduced in patients with non-familial hypercholesterolemia (SMD: -0.34 mm and p = 0.002) and in patients with secondary prevention (SMD: -0.38 mm and p = 0.002). The low-density lipoprotein cholesterol level was significantly reduced in the ezetimibe/statin group (SMD: -0.58 mg/dL and p < 0.001). Conclusions: The effect of ezetimibe on CIMT reduction was shown in non-familial hypercholesterolemia and secondary prevention. These results suggest that the efficacy of ezetimibe may vary with potential CIMT reduction benefits in certain subpopulations.

Keywords: atherosclerosis; cardiovascular disease; ezetimibe; intima-media thickness; stroke.

Figure 1

Flow diagram for the studies evaluated and included in systemic review and meta-analysis of randomized controlled trails.

Figure 2

Forest plot: the effects of ezetimibe/statin on carotid intima-media thickness compared to statin alone. Std: standard; SD: standard deviation; CI: confidence interval; and I²: I-squared; green square: average for each study, black rhomb: overall average [13,15,17,18,19].

Figure 3

Subgroup analyses: the effects of ezetimibe on carotid intima-media thickness. (A) Subgroup analysis depending on the presence or absence of FH. (B) Subgroup analysis depending on prevention type—primary, or secondary prevention. Std: standard; SD: standard deviation; CI: confidence interval; I²: I-squared; and FH: familial hypercholesterolemia; green square: average for each study, black rhomb: overall average average [13,15,17,18,19].

Figure 4

Forest plots: the effects of ezetimibe/statin on lipid profile compared to statin alone, established by presence or absence of FH. (A) LDL-C, (B) TG, and (C) HDL-C. Std: standard; SD: standard deviation; CI: confidence interval; I²: I-squared; LDL-C: low-density lipoprotein cholesterol; TG: triglyceride; HDL-C: high-density lipoprotein cholesterol; and FH: familial hypercholesterolemia; green square: average for each study, black rhomb: overall average [13,15,17,18,19].