Erectile Dysfunction Drugs Improve Survival in Diabetic

From Medscape Education Clinical Briefs
Erectile Dysfunction Drugs Improve Survival in Diabetic Men CME/CE

News Author: Marlene Busko
CME Author: Charles P. Vega, MD


Clinical Context

Few areas in the field of endocrinology are as controversial as the application of exogenous testosterone among men without primary hypogonadism. The potential benefits of testosterone therapy among older men have been promoted to the healthcare community and lay public, yet concern remains regarding the cardiovascular safety of exogenous testosterone, particularly among high-risk older men.

Men with diabetes would appear to be in such a high-risk group, but a longitudinal study by Muraleedharan and colleagues, which was published in the October 21, 2013, issue of the European Journal of Endocrinology, suggests that exogenous testosterone might actually reduce the risk for mortality among men with diabetes. Researchers observed a cohort of 581 men with type 2 diabetes for a mean duration of 5.8 years.

They found that low levels of serum testosterone were associated with a twofold increase in the risk for mortality in the study cohort. However, the application of exogenous testosterone obviated the increased risk for death associated with low testosterone levels.

This salutary effect of exogenous testosterone might be explained because of known beneficial effects of testosterone on glucose metabolism, but testosterone has multiple other effects in the body as well.
Recent research presented at the 75th Scientific Sessions of the American Diabetes Association (ADA) provides further data regarding the effects of testosterone treatment on mortality among men with diabetes.
Another study featured at the meeting evaluated whether phosphodiesterase-5 (PDE5) inhibitors, used primarily to treat erectile dysfunction, might have an impact on mortality outcomes among men with diabetes as well.

Study Synopsis and Perspective

In a preliminary study of men with type 2 diabetes, the use of PDE5 inhibitors was associated with reduced all-cause mortality risk, 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 for diagnosed hypogonadism -- both independently reduce mortality risks.

The 2 studies were presented during a late-breaking poster session at the recent 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 for 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 finding 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 outcomes.

The first trial, a retrospective analysis of data from 42 general practices in Cheshire, United Kingdom, included 7860 men 40 to 89 years old who had been diagnosed with type 2 diabetes before January 1, 2007, and who were followed up for approximately 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), tadalafil (Cialis), and vardenafil (Levitra).

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%).

Also, even after adjustment for multiple confounders -- age; estimated glomerular filtration rate; 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, 0.83; P = .038).

Also 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 (hazard ratio, 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 (51/161 men; 24.1%) compared with men with a previous MI who were not receiving a PDE5 inhibitor (332/1066 men; 31%).

The researchers speculate that this improved survival outcome 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 PDE5 inhibitors (because of the suggestion that the latter are associated with reduced mortality risk).

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 5 primary care practices in Manchester, England, from 2007 to 2009; these men were observed for 5.8 years.

This study included 320 patients with normal levels of total testosterone (>12 nmol/L) and 362 patients with low testosterone levels (≤12 nmol/L), who were not treated with testosterone therapy. Another 175 patients with low testosterone levels were treated with testosterone therapy. Patients took PDE5 inhibitors as required, with approximately 20% of the population receiving these drugs.

In the subgroup of 682 patients who were not receiving 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.

PDE5 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 Rates, Too

In the same study, men treated with testosterone were 5.4 years younger and had a higher body mass index, blood pressure, glycated hemoglobin levels, and baseline cholesterol levels 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 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 prospective study is the first 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 the risk for 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.

Also, it is important to note the clear message from this study in 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 adverse 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 for mortality]," Dr Hackett concluded.

The studies by Hackett and colleagues were funded by an unrestricted grant from Bayer. Dr Hackett receives research support from Bayer HealthCare and is a speaker for Bayer, Lilly, and Besins Healthcare. Dr Heald is a speaker for Bayer and Lilly.

American Diabetes Association (ADA) 2015 Scientific Sessions; June 7, 2015; Boston, Massachusetts. Abstract 7-LB, Abstract 9-LB
Study Highlights

First study (Abstract 7-LB):
This research analyzed medical records of 7860 men with type 2 diabetes diagnosed before 2007 in one of 42 general practice sites in the United Kingdom.
The main study outcome was the effect of treatment with PDE-5 inhibitors on the risk for mortality among men who experienced an acute MI.
Among all men with a history of an acute MI, the rate of mortality among men receiving PDE-5 inhibitors was lower compared with that of men who had not received PDE-5 inhibitors (24.1% vs. 31.1%, respectively).
432 men experienced a MI during the follow-up period. The hazard ratio for overall mortality among these men associated with PDE-5 inhibitor use was 0.5 (95% confidence interval [CI], 0.29 - 0.85).
Second study (Abstract 9-LB):
The research queried diabetes registers from 5 general practices in the United Kingdom during 2007 to 2009. Specifically, the study focused on men with type 2 diabetes and low serum testosterone levels, as defined by a total testosterone level of 12 nmol/L or less and a free testosterone level of 0.25 nmol/L or less.
Men were divided into one of 3 groups based on their clinical profile: normal testosterone level, untreated low testosterone level, or low testosterone level treated with long-acting testosterone undecanoate. This final group was receiving treatment as part of a separate randomized clinical trial.
Men were followed up for a mean of 5.8 years for overall mortality. A multivariate analysis was performed to reduce confounders related to the main study question of the effects of testosterone levels and testosterone treatment on the risk for death.
857 men provided data for the study. The mean age of the participants was 63 years.
Men treated with testosterone were younger and had higher blood pressure, body mass index, glycated hemoglobin levels, and total cholesterol levels. They were also more likely to be receiving a PDE5 inhibitor.
Unadjusted mortality rates in the normal testosterone, untreated low testosterone, and testosterone treatment cohorts were 11.2%, 16.8%, and 3.4%, respectively.
The adjusted hazard ratio for death in comparing men receiving testosterone treatment vs those with untreated low testosterone levels was 0.33 (95% CI, 0.12 - 0.92). The respective hazard ratio in comparing men with normal testosterone levels vs those with untreated low levels was 0.62 (95% CI, 0.41 - 0.95).
PDE5 inhibitors were also associated with a survival benefit, as were statins.
These retrospective analyses should be interpreted with some caution, as there is a clear chance for selection bias in both trials. Men perceived as healthier were probably more likely to receive prescriptions for testosterone treatment and PDE5 inhibitors.

Clinical Implications

A previous study by Muraleedharan and colleagues found that low testosterone levels among men with type 2 diabetes were associated with a twofold increase in mortality compared with normal testosterone levels, but treatment with exogenous testosterone therapy obviated the increased risk for mortality associated with low testosterone levels.
The current limited data by Hackett and colleagues, which were presented at the ADA 2015 Scientific Sessions, suggest that exogenous testosterone therapy and PDE5 inhibitors are both associated with improved mortality outcomes among men with type 2 diabetes. There were insufficient data to prove causation.
Implications for the Healthcare Team: Men with diabetes may derive more benefit than symptoms and performance alone with PDE5 inhibitors and exogenous testosterone therapy. Health educators and professionals should follow research in this area to appropriately identify and treat patients.