Chronic Vardenafil Treatment Has CV Benefits in Type 2 Diabetes

Becky McCall

May 20, 2015

DUBLIN — Chronic treatment with the phosphodiesterase-5 (PDE-5) inhibitor vardenafil (Levitra, Bayer/GlaxoSmithKline) for 6 months in men with type 2 diabetes is safe, improves both endothelial function and measures of hemodynamic function, and reduces inflammatory markers.

And a novel and unexpected finding of the treatment for erectile dysfunction was an improvement in testosterone serum levels in a subset of hypogonadal diabetic men.

"Importantly, the clinical trial was originated by investigators, not a drug company," Dr Daniele Santi (University of Modena, Italy), lead investigator, told Medscape Medical News. Dr Santi received the European Society of Endocrinology Young Investigator Award for his study, presented here at the European Congress of Endocrinology (ECE) 2015.

"Vardenafil was found to be safe in chronic use, which is important because there is a general fear in taking this type of drug long term," he continued.

"The results suggest a possible new use for the drug…to improve endothelial health. With further studies, this might relate to reduction in mortality, and this would have even wider implications."

Dr Santi and his colleagues aimed to investigate the effect on endothelial function of chronic treatment with vardenafil for 6 months in type 2 diabetes patients, as well as the effects for a further 6 months after treatment withdrawal.

The trial also retrospectively evaluated the gonadal status of men in the study. "I think this is the most interesting finding, because this has never been assessed before in such patients," highlighted Dr Santi.

Asked to comment, Dr Andrea Isidori (Sapienza University of Rome, Italy) explained the importance of the work, saying that despite the increased use of antidiabetic drugs, many patients with type 2 diabetes still die due to cardiovascular events, at a rate that is two to four times higher than nondiabetic matched controls.

"Endothelial dysfunction is the hallmark of cardiovascular complications of type 2 diabetes. In their clinical trial, Dr Santi and his colleagues demonstrated that it is possible to target endothelial dysfunction independently of glycemic control in patients with type 2 diabetes," he told Medscape Medical News.

"Their work expands previous observations on the cardiovascular protective effects of chronically administered PDE-5 inhibitors, although not all trials converge," he continued.

"The differences are probably related to the peculiar damage occurring in diabetes compared with other vascular disorders. In this context, the study by Dr Santi brings novel evidence that deserves attention."

Interleukin-6 Levels Reduced by 60% Over 6 Months of Treatment

Dr Santi said the motivation for this study came from a previous meta-analysis that had looked at another PDE-5 inhibitor, sildenafil (Viagra, Pfizer), in men with type 2 diabetes and found a significant improvement in endothelial health.

However, this new study is the first to directly look at the effect of vardenafil on endothelial function, as well as observe the effects of 6 months of use of this agent and the effects after withdrawal, including those on the gonads, he noted.

A total of 54 male patients, aged 40 to 65 years, with type 2 diabetes were enrolled in the study. All participants had a body mass index (BMI) less than 35 kg/m2 and had mild or severe erectile dysfunction (International Index of Erectile Function (IIEF-15) < 25).

Of these, 26 and 28 patients were randomized to the vardenafil group and the placebo group, respectively. Patients received 10 mg of vardenafil twice a day for 6 months or placebo, followed by the follow-up phase of 6 months.

The results showed no drug-related adverse events. As expected, 6 months of treatment improved erectile function according to IIEF-15 (P = .049), and likewise an improvement was seen in endothelial-health measures, including flow-mediated dilation (P = .002).

Significant decreases were also seen in intima media thickness (P = .003), fibrinogen (P = .005), white-blood-cell count (P = .018), and red-cell distribution width (P = .028).

"The inflammatory marker interleukin-6 also showed a decrease of greater than 60% over the 6 months of treatment," reported Dr Santi, noting, "This is one of the most important results."

During the 6-month follow-up after treatment withdrawal, the effects on flow-mediated dilation decreased, but inflammatory markers retained the levels of improvement seen during the treatment phase, suggesting "a long-term effect on inflammation," said Dr Santi.

Unexpected Finding — Testosterone Levels Rise

Finally, Dr Santi highlighted the improvement in testosterone levels in men who were hypogonadal at baseline. The researchers suggest this effect is possibly due to improved microcirculation in the testes.

"This is the first study to find elevation in testosterone levels," he said. "Vardenafil was found to improve levels of testosterone from below 10.4 nmol/L to about 12 nmol/L."

Dr Santi observed that hypogonadism was not one of the inclusion criteria. "Our results relating to testosterone were found upon retrospective analysis. We found 22% of our cohort were hypogonadal at baseline, so our finding applies to this small subgroup, but these results could open new horizons for work in the field of hypogonadism," he commented.

Dr Jens Christensen (University of Aarhus, Denmark), who moderated the session, said, "The fact that testosterone increased is inexplicable for the time being, so that needs further investigation."

Dr Christensen added that there were some other interesting observations that may or may not prove to be important in the future. "However, there were some omissions in the study," he pointed out. "For example, it would have been helpful if there had been close monitoring of the impact on blood pressure.

"Also, it was tested only in men, and I think it should have been done in women as well. Then it would have demonstrated a greater ascertainment of the double-blind value of this study — because men will feel the impact and know they are taking the compound rather than placebo."

Bayer provided vardenafil for the trial. Dr Santi and Dr Christensen have declared no relevant financial relationships. Dr Isidori has received consultation fees and honoraria from Viropharma/Shire, Novartis, Otsuka, and Menarini.

European Congress of Endocrinology 2015. May 17, 2015; Dublin, Ireland. Abstract 37 OC4.3

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