Elsevier

Atherosclerosis

Volume 223, Issue 1, July 2012, Pages 78-85
Atherosclerosis

Review
Meta-analysis of the effects of statin therapy on endothelial function in patients with diabetes mellitus

https://doi.org/10.1016/j.atherosclerosis.2012.01.031Get rights and content

Abstract

Background

Controversies exist among trials reporting the effects of statins on endothelial dysfunction in patients with diabetes mellitus (DM). Therefore, we performed a meta-analysis to determine whether statin therapy could improve endothelial dysfunction in patients with DM.

Methods

PubMed, Cochrane and Embase were searched for randomized controlled trials of statins. Only trials reporting changes in flow-mediated dilatation (FMD) were included in this analysis. A meta-analysis was performed to assess the relationship between statin therapy and improvements in endothelial dysfunction. Meta-regression and subgroup analyses were done to identify sources of heterogeneity.

Results

Ten statin studies (845 patients) were included in this analysis. Statin therapy significantly improved FMD in patients with DM [weighted mean difference (WMD): 0.94%; 95% CI: 0.38%, 1.5%; P < 0.001]. Although heterogeneity among trials was found (I2: 67%), no significant publication bias was detected. Subgroup analyses showed that patients did not benefit from statin therapy if their body mass index (BMI) was > 27.6 kg/m2 (four trials; I2: 0%; WMD: 0.11%; 95% CI: −0.47%, 0.70%; P = 0.70). However, FMD was significantly improved among patients with BMI ≤27.6 kg/m2 (five trials; I2: 14%; WMD: 1.52%; 95% CI: 1.19%, 1.85%; P < 0.001). Type 1 diabetes, younger age, lower baseline blood lipid levels and blood pressure were all associated with improvements in FMD. The meta-regression analysis yielded similar results.

Conclusion

Statins significantly improved the FMD only in patients with better endothelial functions. The use of FMD in evaluating therapeutic outcomes should be careful in populations at high risk.

Introduction

The incidence of diabetes mellitus (DM) is rapidly increasing, in part because of the aging population and changes in lifestyle. By 2030, it is estimated that 366 million people worldwide will have DM [1]. DM is frequently associated with a dyslipidemic triad consisting of elevated triglyceride and low-density lipoprotein-cholesterol (LDL-c) levels, and decreased high-density lipoprotein-cholesterol (HDL-c) levels [2]. Dyslipidemia can result in endothelial dysfunction [3], [4].

A healthy vascular endothelium plays a crucial role in maintaining vascular homeostasis. Endothelial dysfunction is an early pathophysiologic feature of atherosclerosis and is an independent predictor for cardiovascular diseases. Lowering LDL serum levels by statin therapy was found to improve endothelial function in animal studies [5]. The mechanisms underlying these beneficial effects of statins include upregulation of endothelial nitric oxide (NO) synthase expression, increased NO production, enhanced anti-inflammatory activity, and favorable effects on plaque stability [6], [7]. However, controversies still exist between clinical studies. For example, some studies have revealed that statin therapy cannot improve endothelial function in patients with DM [8], [9], whereas others have shown that statins significantly improve endothelial function in patients with DM [10], [11], [12]. Therefore, it is necessary to re-evaluate the effects of statins on endothelial function in patients with DM.

Flow-mediated dilatation (FMD) is widely used as a clinical marker of endothelial function. FMD is mainly determined by noninvasive ultrasound assessment of the arterial endothelial responsiveness, a method that is repeatable, reproducible and closely correlated with invasively measured endothelial function [13]. In the present study, we sought to retrieve all published, randomized, placebo-controlled clinical trials of statin therapy in patients with DM and performed a meta-analysis to evaluate the effect of statin therapy on FMD in these patients.

Section snippets

Search strategy

This study was designed according to the Quality of Reporting of Meta-analyses (QUORUM) statement [14]. Two researchers (Gong and Zhang) independently searched PubMed (http://www.ncbi.nlm.nih.gov/pubmed; date range: 1950 to Aug 2011), Embase (http://www.embase.com; date range: 1966 to Aug 2011), and the Cochrane Central Register of Clinical Trials (Cochrane Library, Issue 8 of 12, Aug 2011). Both researchers also reviewed the reference lists of relevant articles and bibliographies of original

Study selection

The method used to select the studies is shown in Fig. 1. Our search of PubMed, Embase and the Cochrane Library, and manual review of articles cited in the identified and related publications, initially retrieved 1694 publications. Of these, 877 were excluded because they were review articles/not clinical trials, or because the objectives of the articles were not related to our present meta-analysis. Animal studies (n = 113), cellular studies (n = 229), and studies not measuring FMD (n = 335) were

Discussion

In this meta-analysis, we pooled and analyzed data from 10 clinical trials comparing statin therapy with placebo in patients with DM. The results of our analysis revealed that statins can significantly improve overall endothelial dysfunction, as evidenced by improvements in FMD. We also performed subgroup and meta-regression analyses because of significant heterogeneity. In subgroup analysis, patients with BMI  27.6 kg/m2 showed significant improvements in FMD, whereas patients with BMI > 27.6 kg/m2

Conflict of interest

None declared.

Acknowledgment

This study was funded by grants from the Ministry of Science & Technology of China (2010CB732601).

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