Marlene Busko

June 24, 2015

BOSTON — In a preliminary study of men with type 2 diabetes, the use of phosphodiesterase type-5 (PDE5) inhibitors was associated with reduced all-cause mortality, even in men who had a previous myocardial infarction (MI), during a 5-year follow-up.

A second study, with a few of the same coauthors, came up with similar results in a different population of men with type 2 diabetes, some of whom were also receiving testosterone therapy. This showed that PDE5 inhibitors and testosterone — in a population appropriately receiving the male hormone due to diagnosed hypogonadism — both independently reduce mortality.

The two studies were presented during a late-breaking poster session at the recent American Diabetes Association (ADA) 2015 Scientific Sessions.

The findings appear contrary to what might be expected, coauthor of both studies, Dr Adrian H Heald (University of Manchester, United Kingdom), told Medscape Medical News.

Because "erectile dysfunction is a marker of endothelial dysfunction — small-vessel dysfunction — and therefore, if anything, [men with erectile dysfunction] would be more likely to have a [potentially fatal] myocardial infarction, and the fact that we pushed [the risk of mortality] the other way is, I think, a pretty significant finding," he said.

However, this line of research has important caveats, Dr Simon G Anderson (University of Manchester), lead author of the first study (which did not involve testosterone), cautioned. For example, the researchers lacked information about other relevant factors that could contribute to longevity, such as frequency of sexual activity or lack of depression.

Diabetic Men Taking vs Not Taking Drugs for Erectile Dysfunction

Animal studies have shown that PDE5 inhibitors are cardioprotective and reduce arrhythmias, Dr Anderson explained. However, this has not been well studied in humans. The researchers aimed to determine whether men with type 2 diabetes who were taking PDE5 inhibitors had improved survival.

The first trial, a retrospective analysis of data from 42 general practices in Cheshire, United Kingdom, included 7860 men aged 40 to 89 who had been diagnosed with type 2 diabetes prior to January 1, 2007 and who were followed for about 5 years.

A total of 1359 men (22.8%) had been prescribed a PDE5 inhibitor.

PDE5 inhibitors licensed for use in the United Kingdom include sildenafil (Viagra, Pfizer), tadalafil (Cialis, Lilly/ICOS), and vardenafil (Levitra, Bayer/GlaxoSmithKline).

This group had a lower risk of dying during the 5-year follow-up compared with their peers who did not receive a PDE5 inhibitor (18% vs 25%).

And even after adjustment for multiple confounders — age, estimated glomerular filtration rate (eGFR), history of MI, smoking, systolic blood pressure, and use of a statin, beta-blocker, aspirin, and metformin — the men who were taking a drug for erectile dysfunction still had a lower risk of dying from all causes during follow-up (hazard ratio [HR], 0.83; P = .038).

And notably, in the cohort of 432 men who had a new MI during follow-up, those who had been receiving a PDE5 inhibitor were 38% less likely to die from the MI, compared with their peers, after adjustment for the same multiple confounders (HR, 0.62; P = .001).

Similarly, among the men who had had a previous MI, fewer men who were receiving a PDE5 inhibitor died during follow-up (51 of 161 men; 24.1%) compared with men with a previous MI who were not receiving a PDE5 inhibitor (332 of 1066 men; 31%).

The researchers speculate that this improved survival in patients taking a PDE5 inhibitor may be partly explained by the fact that these drugs decrease the PDE5-mediated breakdown of cyclic GMP, with the latter being cardioprotective.

Nevertheless, this "does require further work in a larger cohort to look at this," Dr Anderson admitted

Striking Reduction in Second Study

The second study was designed to investigate the effect of testosterone-replacement therapy on mortality after adjustment for use of PDE 5 inhibitors (because of the suggestion that the latter are associated with reduced mortality).

Dr Geoffrey I Hackett (University of Bedfordshire, United Kingdom) and colleagues performed a prospective longitudinal study in 857 men with type 2 diabetes recruited from five primary-care practices in Manchester, England from 2007 to 2009, who were followed for 5.8 years.

This study included 320 patients with normal total testosterone (> 12 nmol/L) and 362 patients with low testosterone (< 12 nmol/L), who were not treated with testosterone therapy. Another 175 patients with low testosterone were treated with testosterone therapy. Patients took PDE5 inhibitors as required, with about 20% of the population using them.

In the subgroup of 682 patients who were not on testosterone therapy, men taking a PDE5 inhibitor had a striking 15-fold lower risk of dying within 5.8 years than their peers (odds ratio, 0.060; P = .007), after adjustment for age and statin treatment.

PDE 5 inhibitor use has been restricted in the United Kingdom, because of costs, and also because of "scare stories" about the risks, Dr Hackett noted.

"But a newly diagnosed [man with type 2 diabetes] has a 75% chance of developing [erectile dysfunction], and those who haven't got [erectile dysfunction] just haven't got it yet."

"I firmly believe, particularly now that we have generic PDE5 inhibitors, that in a few years' time, [a PDE5 inhibitor] will be in the mix for something that you're given along with your statin and your ramipril at the time of diagnosis."

Testosterone Reduced Mortality Too

In the same study, men treated with testosterone were 5.4 years younger and had a higher BMI, blood pressure, HbA1c, and baseline cholesterol and were twice as likely to be taking a PDE5 inhibitor (36.6% vs 15.5%) as men who were not receiving testosterone therapy.

Among men taking testosterone but not taking PDE5 inhibitors, testosterone therapy was associated with a 62% reduction in mortality (P = .027) during follow-up, after adjustment for age and statin treatment.

Thus, according to Dr Hackett, this is the first prospective study on a population with type 2 diabetes that has shown that testosterone-replacement therapy — appropriately given in men with definitely established hypogonadism — and the use of a PDE5 inhibitor independently reduce all-cause mortality.

Only 80 patients took both testosterone and PDE5 inhibitors, so the numbers were not large enough to look at whether there was any combined, synergistic effect of using both, Dr Hackett said.

And it's important to note the clear message from this study with regard to testosterone, he stressed, noting the controversy that has surrounded use of this treatment.

The US Food and Drug Administration recently issued a warning about testosterone therapy and the potential for cardiovascular side effects, particularly in older men, although the European Medicines Agency did not find sufficient evidence to draw the same conclusion.

"Proper diagnosis and treatment of testosterone deficiency in diabetes reduces risk, compared with the nonsense papers published [that indicate increased risk of mortality]," Dr Hackett concluded.

The study by Hackett et al was funded by an unrestricted grant from Bayer. Dr Hackett receives research support from Bayer Healthcare and is a speaker for Bayer, Lilly, and Besins. Dr Heald is a speaker for Bayer and Lilly.

American Diabetes Association 2015 Scientific Sessions; June 7, 2015; Boston, Massachusetts. Abstract 7-LB, Abstract 9-LB

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