AIMS: Statins are known to influence the status of adipokines, which play a key role in the pathophysiology of cardiometabolic diseases. As the effect of ezetimibe as an add-on to statin therapy on the impact of statins on plasma adipokines levels is currently unclear, the aim of the present study was to investigate this through a meta-analysis of controlled trials. METHODS: A systematic review was performed, followed by a bibliographic search in PubMed, Medline, SCOPUS, Web of Science and Google Scholar databases. Quantitative data synthesis was performed using a fixed- or random-effects model (based on the level of interstudy heterogeneity) and the generic inverse variance weighting method. Effect sizes were expressed as standardized mean difference (SMD) and 95% confidence interval (CI). RESULTS: Meta-analysis of 23 controlled trials did not suggest any significant effect of adding ezetimibe on top of statin therapy on plasma concentrations of adiponectin (SMD 0.34, 95% CI -0.28, 0.96; P = 0.288), leptin (SMD -0.75, 95% CI: -2.35, 0.85; P = 0.360), plasminogen activator inhibitor 1 (SMD -1.06, 95% CI: -2.81, 0.69; P = 0.236) and interleukin 6 (SMD 0.30, 95% CI: -0.08, 0.67; P = 0.124). However, significantly greater reductions in plasma concentrations of tumour necrosis factor α (TNF-α) (SMD -0.48, 95% CI -0.87, -0.08; P = 0.018) were achieved with ezetimibe/statin combination therapy. CONCLUSIONS: The results suggested that ezetimibe add-on to statin therapy is associated with an enhanced TNF-α-lowering effect compared with statin monotherapy. Owing to the emerging role of TNF-α in the pathogenesis of metabolic disorders, further investigations are required to unveil the translational relevance of this TNF-α-lowering effect.

Biotechnology Research Center Mashhad University of Medical Sciences Mashhad Iran School of Medicine University of Western Australia Perth WA Australia

Centre of Diabetes and Metabolic Diseases Department of Internal Medicine and Therapeutics University of Pavia and Fondazione IRCCS Policlinico San Matteo Pavia Italy Center for the Study of Endocrine Metabolic Pathophysiology and Clinical Research University of Pavia Pavia Italy Molecular Medicine Laboratory University of Pavia Pavia Italy

Centre of Diabetes and Metabolic Diseases Department of Internal Medicine and Therapeutics University of Pavia and Fondazione IRCCS Policlinico San Matteo Pavia Italy PhD School in Experimental Medicine University of Pavia Pavia Italy

Faculty of Pharmacy in Hradec Kralove Department of Biological and Medical Sciences Charles University Hradec Kralove Czech Republic

Metabolic and Atherosclerosis Research Center Cincinnati OH USA

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