ReviewMeta-analysis of the effects of statin therapy on endothelial function in patients with diabetes mellitus
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).
References (44)
- et al.
Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force
J Am Coll Cardiol
(2002) - et al.
Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of reporting of meta-analyses
Lancet
(1999) - et al.
Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses?
Lancet
(1998) - et al.
Variance imputation for overviews of clinical trials with continuous response
J Clin Epidemiol
(1992) - et al.
Meta-analysis in clinical trials
Control Clin Trials
(1986) - et al.
Atorvastatin but not l-arginine improves endothelial function in type I diabetes mellitus: a double-blind study
J Am Coll Cardiol
(2000) - et al.
Effect of pravastatin on endothelial function in patients with coronary artery disease (cholesterol-independent effect of pravastatin)
Am J Cardiol
(2001) - et al.
Impaired endothelium-dependent vasodilation in patients with essential hypertension: evidence that the abnormality is not at the muscarinic receptor level
J Am Coll Cardiol
(1994) - et al.
Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial
Lancet
(2004) - et al.
Is the association between flow-mediated dilation and cardiovascular risk limited to low-risk populations?
J Am Coll Cardiol
(2005)
Influence of age, risk factors, and cardiovascular and renal disease on arterial stiffness: clinical applications
Am J Hypertens
Effect of statins alone versus statins plus ezetimibe on carotid atherosclerosis in type 2 diabetes: the SANDS (Stop Atherosclerosis in Native Diabetics Study) trial
J Am Coll Cardiol
Global prevalence of diabetes: estimates for the year 2000 and projections for 2030
Diabetes Care
Beyond low-density lipoprotein: addressing the atherogenic lipid triad in type 2 diabetes mellitus and the metabolic syndrome
Am J Cardiovasc Drugs
Endothelial dysfunction in obesity: etiological role in atherosclerosis
Curr Opin Endocrinol Diabetes Obes
Hypercholesterolemia-associated endothelial progenitor cell dysfunction
Ther Adv Cardiovasc Dis
Improvement of age-related endothelial dysfunction by simvastatin: effect on NO and COX pathways
Br J Pharmacol
Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase
Proc Natl Acad Sci USA
Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators
Circulation
Intense cholesterol lowering therapy with a HMG-CoA reductase inhibitor does not improve nitric oxide dependent endothelial function in type-2-diabetes—a multicenter, randomised, double-blind, three-arm placebo-controlled clinical trial
Exp Clin Endocrinol Diabetes
The effect of statin therapy on endothelial function in type 2 diabetes without manifest cardiovascular disease
Diabetes Care
Statin therapy improves brachial artery vasodilator function in patients with Type 1 diabetes and microalbuminuria
Diabet Med
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These authors contributed equally to this work.