title: Therapy of endocrine disease. Effects of chronic use of phosphodiesterase inhibitors on endothelial markers in type 2 diabetes mellitus: a meta-analysis.
abstract: OBJECTIVE
  Diabetes mellitus (DM) is associated with endothelial dysfunction, reducing nitric oxide-dependent vasodilation, and increasing production of pro-inflammatory factors, leading to an increased risk of long-term cardiovascular disease. As the effects of phosphodiesterase 5 inhibitors (PDE5i) on endothelial function have not been systematically investigated, we conducted a meta-analysis of available randomized clinical trials (RCTs).
  
  
  METHODS
  A thorough search of the literature was carried out. Relevant studies were considered according to RCT study design, enrollment of men with type 2 DM, chronic administration of PDE5i, and evaluation of endothelial function through both hemodynamic and endothelial inflammation-related parameters.
  
  
  RESULTS
  Fifteen studies fulfilled the eligibility criteria but only six RCTs met the inclusion criteria and were analyzed for 476 diabetic men, 239 randomized to Sildenafil, and 237 to placebo respectively. Four RCTs evaluated flow-mediated dilation (FMD), demonstrating a weighted mean increase of 2.19% (95% CI 0.48 to 3.90). This result showed a high heterogeneity (I(2): 98%). Thus, a further sub-group meta-analysis was performed and this analysis confirmed a significant, Sildenafil-related FMD improvement. Sildenafil improved endothelin 1 and high sensitivity C-reactive protein by ∼-0.94 pg/ml and -0.36 mg/l, respectively, not reaching statistical significance (P=0.69 and P=0.22 respectively). Finally, Sildenafil administration significantly reduced serum levels of interleukin 6 (IL6, -0.82 pg/ml; 95% CI -1.58 to -0.07).
  
  
  CONCLUSIONS
  This meta-analysis suggests a beneficial effect of chronic PDE5i administration on endothelial function. Chronic Sildenafil administration seems to improve hemodynamic (FMD) and serum pro-inflammatory makers (IL6) in diabetic men. Larger studies are needed to confirm the effects of chronic PDE5i on endothelial function.
authors.affiliation: Unit of EndocrinologyDepartment of Biomedical Metabolic and Neural Sciences. University of Modena and Reggio Emilia, ItalyAzienda USL of ModenaItalySapienza University of RomeDepartment of Experimental MedicineDepartment of Medical SciencesIRCSS San Raffaele, Rome, Italy Unit of EndocrinologyDepartment of Biomedical Metabolic and Neural Sciences. University of Modena and Reggio Emilia, ItalyAzienda USL of ModenaItalySapienza University of RomeDepartment of Experimental MedicineDepartment of Medical SciencesIRCSS San Raffaele, Rome, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Santi
authors.affiliation: Unit of EndocrinologyDepartment of Biomedical Metabolic and Neural Sciences. University of Modena and Reggio Emilia, ItalyAzienda USL of ModenaItalySapienza University of RomeDepartment of Experimental MedicineDepartment of Medical SciencesIRCSS San Raffaele, Rome, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giannetta
authors.affiliation: Unit of EndocrinologyDepartment of Biomedical Metabolic and Neural Sciences. University of Modena and Reggio Emilia, ItalyAzienda USL of ModenaItalySapienza University of RomeDepartment of Experimental MedicineDepartment of Medical SciencesIRCSS San Raffaele, Rome, Italy.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Isidori
authors.affiliation: Unit of EndocrinologyDepartment of Biomedical Metabolic and Neural Sciences. University of Modena and Reggio Emilia, ItalyAzienda USL of ModenaItalySapienza University of RomeDepartment of Experimental MedicineDepartment of Medical SciencesIRCSS San Raffaele, Rome, Italy.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Vitale
authors.affiliation: Unit of EndocrinologyDepartment of Biomedical Metabolic and Neural Sciences. University of Modena and Reggio Emilia, ItalyAzienda USL of ModenaItalySapienza University of RomeDepartment of Experimental MedicineDepartment of Medical SciencesIRCSS San Raffaele, Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Aversa
authors.affiliation: Unit of EndocrinologyDepartment of Biomedical Metabolic and Neural Sciences. University of Modena and Reggio Emilia, ItalyAzienda USL of ModenaItalySapienza University of RomeDepartment of Experimental MedicineDepartment of Medical SciencesIRCSS San Raffaele, Rome, Italy Unit of EndocrinologyDepartment of Biomedical Metabolic and Neural Sciences. University of Modena and Reggio Emilia, ItalyAzienda USL of ModenaItalySapienza University of RomeDepartment of Experimental MedicineDepartment of Medical SciencesIRCSS San Raffaele, Rome, Italy manuela.simoni@unimore.it.
authors.forename: Manuela
authors.initials: M
authors.lastname: Simoni
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004700:Endocrine System Diseases / Q000097:blood / Q000188:drug therapy*; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic
chemical_list: D015850:Interleukin-6; D010726:Phosphodiesterase Inhibitors