Elsevier

Metabolism

Volume 64, Issue 11, November 2015, Pages 1466-1476
Metabolism

Meta-analysis
Does statin therapy reduce plasma VEGF levels in humans? A systematic review and meta-analysis of randomized controlled trials

https://doi.org/10.1016/j.metabol.2015.08.002Get rights and content

Abstract

Background

The effect of statins on plasma concentrations of vascular endothelial growth factor (VEGF), the main angiogenic growth factor with pro-inflammatory and atherogenic properties, is controversial. A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to obtain a conclusive result in humans.

Methods

PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases were searched to identify RCTs investigating the impact of statins on plasma VEGF concentrations. A random-effects model and the generic inverse variance method were used for quantitative data synthesis. Meta-regression, sensitivity analysis and publication bias assessments were performed using standard methods.

Results

Eight RCTs examining the effects of statins on plasma VEGF concentrations were included. Meta-analysis suggested a significant reduction of plasma VEGF levels following statin therapy (weighed mean difference: − 19.88 pg/mL, 95% CI: − 35.87, − 3.89, p = 0.015). VEGF reductions were observed in the subsets of trials with treatment durations ≥ 4 weeks (− 19.54, − 37.78, − 1.30, p = 0.036), LDL-C reductions ≥ 50 mg/dL (− 28.59, − 43.68, − 13.50, p < 0.001), lipophilic statins (− 22.31, − 40.65, − 3.98, p = 0.017), and diseased populations (− 21.08, − 39.97, − 2.18, p = 0.029), but not in the opposite subsets. Meta-regression also suggested a significant association between changes in plasma VEGF levels and LDL-C changes, treatment duration, but not molar dose of statins.

Conclusions

These results suggest a significant reduction in plasma VEGF concentrations following statin therapy. This effect depends on duration of treatment, LDL-lowering activity, lipophilicity of statins, and health status of studied individuals. Further RCTs are needed to explore if the VEGF reduction is implicated in the statin benefits on cardiovascular outcomes.

Introduction

Vascular permeability, vasculogenesis and angiogenesis are regulated by a complex interplay among several growth factors and their associated receptors. In this process, vascular endothelial growth factor (VEGF) family and its receptors play an essential role [1], [2]. The VEGF family consists of different isoforms with several subtypes; each isoform performs a different role in the endothelial and vascular physiology and pathology, as comprehensively reviewed [1], [2], [3], [4]. In particular, VEGF is involved in vascular development, integrity, homeostasis, thrombogenicity modulation, recruitment of hematopoietic precursors and migration of monocytes and macrophages. The angiogenic, permeability-enhancing and pro-inflammatory properties of VEGF determine its role in pathological conditions, such as cancer, ischemia and inflammation [1], [2], [3], [4]. At a cardiovascular level, VEGF is implicated in the progression of atherosclerosis, instability of atherosclerotic plaque through induction of neoangiogenesis inside the plaque, prediction of worse clinical outcomes in acute coronary syndromes, and cardiac hypertrophy through a nitric oxide (NO)-dependent mechanism [1], [2], [3], [4], [5], [6], [7].

Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are known to exert beneficial effects on the clinical outcomes of cardiovascular diseases both by their lipid-lowering, anti-inflammatory, antioxidant and antithrombotic effects and by improving endothelial function, attenuating vascular/myocardial remodeling and stabilizing atherosclerotic plaques [8], [9]. Alternative additional mechanisms by which statins may reduce cardiovascular events beyond their lipid reduction effects may be the modulation of angiogenesis by reducing VEGF levels, as suggested by some case–control human studies performed almost a decade ago [10], [11]. More recently, the effects of different statins on the reduction of VEGF levels have been shown [12], [13], [14], [15], [16], [17], [18], [19]; however, the results of human studies have not been fully conclusive [20], [21], [22], [23], [24], [25], [26]. In addition, some experimental in-vitro and animal studies have suggested a statin-induced stimulation of VEGF expression after endothelial and vascular injuries [27], [28], [29], [30], [31], [32]. Furthermore, there is evidence indicating that statins could directly augment circulating endothelial progenitor cells (EPCs) through mechanisms independent of VEGF [17], [19], [21], [22], [33]. Therefore, at present the role of statins on the VEGF homeostasis is very controversial.

The aim of the present study was to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to clarify the effect of statin treatment on plasma concentrations of VEGF in humans.

Section snippets

Search Strategy

This study was designed according to the guidelines of the 2009 preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement [34]. PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases were searched using the following search terms in titles and abstracts (also in combination with MESH terms): (atorvastatin OR simvastatin OR rosuvastatin OR fluvastatin OR pravastatin OR pitavastatin OR lovastatin OR cerivastatin OR “statin therapy” OR statins) AND (VEGF OR

Flow and Characteristics of Included Studies

With the initial literature search, 235 articles were found (Fig. 1). All these records were screened, and 219 did not meet the inclusion criteria. The full text of the remaining 16 was carefully assessed for eligibility and 8 were selected for the meta-analysis because they satisfied the inclusion criteria. Reasons for rejecting the other 8 articles were: lack of measurements of VEGF concentrations, non-interventional design, short (< 2 weeks) treatment duration, lack of control for statin

Discussion

The results of the present meta-analysis of RCTs showed that statin treatment was associated with a significant reduction in circulating VEGF concentrations. This effect was greater with lipophilic statins and in patients with cardiac diseases, and found to be associated with treatment duration and LDL-lowering effect of statins.

At present, the potential implication of the VEGF family of growth factors in human cardiovascular health is highly controversial. Both vasculogenesis, the in-situ

Conclusions

Findings from the present meta-analysis of RCTs suggested a significant reduction of plasma VEGF concentrations following statin therapy. This effect was found to be dependent on the duration of treatment, health status of the cohort, LDL-lowering activity, and lipophilicity of statins. However, further studies are required to ascertain the presence of any dose–response association for the VEGF-lowering effect of each statin. Future RCTs are also warranted to explore if reduction of plasma VEGF

Author Contribution

AS contributed to conception of the design of the study, acquisition and analysis of data, drafting and revising the paper; MCP contributed to interpretation of data, writing and revising the paper; IG contributed to interpretation of data, writing and revising the paper; SB contributed to interpretation of data writing and revising the paper.

All authors have approved the final version of the manuscript.

Funding

The authors received no funds for the present manuscript.

Conflicts of Interest

None.

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