The Effects of Statin Dose, Lipophilicity, and Combination of Statins plus Ezetimibe on Circulating Oxidized Low-Density Lipoprotein Levels: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

Background. Elevated plasma low-density lipoprotein cholesterol (LDL-C) is the main risk factor for atherosclerotic cardiovascular disease (ASCVD). Statins are the drugs of choice for decreasing LDL-C and are used for the prevention and management of ASCVD. Guidelines recommend that subjects with high and very high ASCVD risk should be treated with high-intensity statins or a combination of high-intensity statins and ezetimibe. The lipophilicity or hydrophilicity (solubility) of statins is considered to be important for at least some of their LDL-C lowering independent pleiotropic effects. Oxidative modification of LDL (ox-LDL) is considered to be the most important atherogenic modification of LDL and is supposed to play a crucial role in atherogenesis and ASCVD outcomes. Objective. The aim of this systematic review and meta-analysis was to find out what are the effects of statin intensity, lipophilicity, and combination of statins plus ezetimibe on ox-LDL. Methods. PubMed, Scopus, Embase, and Web of Science were searched from inception to February 5, 2021, for randomized controlled trials (RCTs). Two independent and blinded authors evaluated eligibility by screening the titles and abstracts of the studies. Risk of bias in the studies included in this meta-analysis was evaluated according to the Cochrane instructions. Meta-analysis was performed using Comprehensive Meta-Analysis (CMA) V2 software. Evaluation of funnel plot, Begg’s rank correlation, and Egger’s weighted regression tests were used to assess the presence of publication bias. Results. Among the 1427 published studies identified by a systematic databases search, 20 RCTs were finally included in the systematic review and meta-analysis. A total of 1874 patients are included in this meta-analysis. This meta-analysis suggests that high-intensity statin treatment is associated with a significant decrease in circulating concentrations of ox-LDL when compared with low-to-moderate treatment (SMD: -0.675, 95% CI: -0.994, -0.357, p < 0.001 ; I 2 : 55.93%). There was no difference concerning ox-LDL concentration between treatments with hydrophilic and lipophilic statins (SMD: -0.129, 95% CI: -0.330, -0.071, p = 0.206 ; I 2 : 45.3%), but there was a significant reduction in circulating concentrations of ox-LDL associated with statin plus ezetimibe combination therapy when compared with statin monotherapy (SMD: -0.220, 95% CI: -0.369, -0.071, p = 0.004 ; I 2 : 0%). Conclusion. High-dose statin or combination of statins with ezetmibe reduces plasma ox-LDL in comparison low-to-moderate intensity statin therapy alone. Statin lipophilicity is not associated with reduction in ox-LDL plasma concentrations.

The Effects of Statin Therapy on Oxidized LDL and Its Antibodies: A Systematic Review and Meta-Analysis

“…Search Strategy. We followed the methods of Jamialahmadi et al as follows [22]. The present systematic review and meta-analysis was designed according to the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [23].…”

“…Data Extraction. We followed the methods of Jamialahmadi et al as follows [22]. After removal of duplicate studies, two independent and blinded authors (JB, MR) evaluated eligibility by screening the titles and abstracts of the studies.…”

“…Quality Assessment. We followed the methods of Jamialahmadi et al as follows [22]. Risk of bias in the studies included in this meta-analysis was evaluated according to the Cochrane instructions [24].…”

Molecular Biological and Clinical Understanding of the Statin Residual Cardiovascular Disease Risk and Peroxisome Proliferator-Activated Receptor Alpha Agonists and Ezetimibe for Its Treatment

“…Ezetimibe, an inhibitor of intestinal cholesterol absorption, can decrease LDL-C, TG, and apo B levels and increase HDL-C levels [ 116 ]. The meta-analysis showed that the combination of statins with ezetimibe as well as high-dose statin reduces plasma ox-LDL in comparison with low-to-moderate-intensity statin therapy alone [ 117 ]. Ezetimibe produced significant and progressive reductions in plasma plant sterol concentrations in patients with sitosterolemia [ 118 ].…”

Investigation of Statin Medication Use in Elderly Patients with Cardiovascular Disease on Regular Physical Examination and the Relationship with Glucolipid Metabolism and Adverse Cardiovascular Prognosis

“…Statins can significantly reduce plasma cholesterol concentration, delay and inhibit the progression of atherosclerosis, and have become one of the drugs of choice for lipid-lowering therapy and antiatherosclerosis in clinical practice [ 10 ]. The results of this study showed that the TC, TG, and LDL-C levels in the medicated group were higher than those in the unmedicated group, and the HDL-C level was higher than that in the unmedicated group, indicating that statin treatment for elderly patients with cardiovascular disease can reduce the body's blood lipid level, which is mainly because statins can play a role in regulating blood lipids by competitively inhibiting enzyme secretion in hepatocytes and reducing the body's methyl dehydroabietate content [ 11 ]. In this study, we found that FBG levels were lower and HbA1c values were lower in the medicated group than in the unmedicated group, indicating that statins can improve glucose metabolism in elderly patients with cardiovascular disease, which is mainly related to the fact that statins can improve insulin resistance and glucose tolerance through their effects.…”