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Daniele Santi, Elisa Giannetta, Andrea M Isidori, Cristiana Vitale, Antonio Aversa and Manuela Simoni

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).

Design

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).

Conclusion

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.

Free access

Daniele Santi, Antonio R M Granata, Alessandro Guidi, Elisa Pignatti, Tommaso Trenti, Laura Roli, Roberto Bozic, Stefano Zaza, Chiara Pacchioni, Stefania Romano, Jerzy Roch Nofer, Vincenzo Rochira, Cesare Carani and Manuela Simoni

Objective

Type 2 diabetes mellitus (T2DM) is associated with endothelial dysfunction, characterized by a reduction of nitric oxide (NO)-mediated relaxation. Phosphodiesterase type 5 inhibitors (PDE5i) improve NO levels. The aim of the study was to investigate whether long-term, chronic treatment with the PDE5i vardenafil improves systemic endothelial function in diabetic men.

Design

A prospective, investigator-initiated, randomized, placebo-controlled, double-blind, clinical trial was conducted.

Methods

In total, 54 male patients affected by T2DM, diagnosed within the last 5 years, and erectile dysfunction were enrolled, regardless of testosterone levels. In all, 26 and 28 patients were assigned to verum and placebo groups respectively. The study consisted of an enrollment phase, a treatment phase (24 weeks) (vardenafil/placebo 10 mg twice in a day) and a follow-up phase (24 weeks). Parameters evaluated were as follows: International Index of Erectile Function 15 (IIEF-15), flow-mediated dilation (FMD), serum interleukin 6 (IL6), endothelin 1 (ET-1), gonadotropins and testosterone (measured by liquid chromatography/tandem mass spectrometry).

Results

IIEF-15 erectile function improved during the treatment (P<0.001). At the end of the treatment both FMD (P=0.040) and IL6 (P=0.019) significantly improved. FMD correlated with serum testosterone levels (R 2=0.299; P<0.001). Testosterone increased significantly under vardenafil treatment and returned in the eugonadal range only in hypogonadal men (n=13), without changes in gonadotropins. Chronic vardenafil treatment did not result in relevant side effects.

Conclusion

This is the first double-blind, placebo-controlled clinical trial designed to evaluate the effects of chronic treatment of vardenafil on endothelial health-related parameters and sexual hormones in patients affected by a chronic disease. Chronically administered vardenafil is effective and improves endothelial parameters in T2DM patient. Moreover, chronic vardenafil therapy improves hypogonadism in diabetic, hypogonadal men.