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Effects of Allopurinol on Endothelial Function: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials

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Abstract

Introduction

Uric acid (UA), the final product of purine catabolism, may be associated with an increased risk of cardiovascular disease.

Aim

The aim of this meta-analysis of randomized placebo-controlled trials was to evaluate whether lowering serum UA (SUA) levels with allopurinol is associated with improved flow-mediated dilation (FMD), a validated marker of early vascular damage.

Methods

A literature search was carried out from inception until 20 June 2017. Meta-analysis was performed using an inverse variance-weighted, random-effects model with standardized mean difference (SMD) as the effect size estimate.

Results

Meta-analysis of data from the ten eligible randomized controlled trials (RCTs), with 670 subjects, suggested a significant increase in FMD following allopurinol treatment (weighted mean difference [WMD] 1.79%, 95% confidence interval [CI] 1.01–2.56, p < 0.001; I 2: 86.77%). The effect size was robust and remained significant after omission of each single study. Subgroup analyses of RCTs based on the administered dose or duration of treatment did not reveal any significant impact of these variables on FMD change. Nor was a significant association found between allopurinol-induced changes in SUA levels and FMD (slope 0.46, p = 0.253), whereas baseline FMD significantly influenced the degree of FMD improvement following allopurinol treatment (slope 0.52, p = 0.022). Nitroglycerin-mediated dilation was not altered by allopurinol treatment (WMD 0.88%, 95% CI − 1.15–2.91, p = 0.395; I 2: 80.88%).

Conclusion

This meta-analysis of available RCTs suggests a significant benefit from allopurinol intake in increasing FMD in humans, independent of its effect on SUA levels.

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Author information

Authors and Affiliations

  1. Department of Medical and Surgical Sciences, University of Bologna, Via Albertoni 15, Bologna, Italy

    Arrigo F. G. Cicero

  2. Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy

    Matteo Pirro

  3. Department of Cardiology, Lipid Disorders Clinic, Royal Perth Hospital, Perth, WA, Australia

    Gerald F. Watts

  4. Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London, London, United Kingdom

    Dimitri P. Mikhailidis

  5. Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, Lodz, Poland

    Maciej Banach

  6. Polish Mother’s Memorial Hospital Research Institute (PMMHRI), Lodz, Poland

    Maciej Banach

  7. Biotechnology Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, 9177948564, Iran

    Amirhossein Sahebkar

  8. School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

    Amirhossein Sahebkar

Authors
  1. Arrigo F. G. Cicero
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  2. Matteo Pirro
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  4. Dimitri P. Mikhailidis
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  6. Amirhossein Sahebkar
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Contributions

AFGC, MP, MB and AS conceived and designed the work and contributed to the drafting of the manuscript. Arrigo F.G. Cicero and Matteo Pirro performed the searches and extracted data. Amirhossein Sahebkar performed the statistical analysis. GFWa, DPM and MB contributed to the interpretation of the work and revised the manuscript critically for important intellectual content. All authors approved the final manuscript and agree to be held accountable for all aspects of the work.

Corresponding author

Correspondence to Amirhossein Sahebkar.

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Conflicts of interest

Prof. Watts has received honoraria for advisory boards and lectures from Amgen, Sanofi, Regeneron, Kowa and MSD. Prof. Banach has served on the speaker’s bureau and as an advisory board member for Amgen, Sanofi, Aventis and Lilly. Prof. Mikhailidis has given talks and attended conferences sponsored by MSD, Libytec and AstraZeneca. No professional writer was involved in the preparation of this meta-analysis.

Funding

This meta-analysis was written independently; no company or institution supported it financially.

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Cicero, A.F.G., Pirro, M., Watts, G.F. et al. Effects of Allopurinol on Endothelial Function: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials. Drugs 78, 99–109 (2018). https://doi.org/10.1007/s40265-017-0839-5

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  • DOI: https://doi.org/10.1007/s40265-017-0839-5

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