Big Trial Reassures on Heart Safety of Testosterone in Men

CHICAGO –Testosterone replacement therapy does not appear to raise the risk for adverse cardiac events among middle-aged and older men with hypogonadism at high risk for heart disease, long-awaited results from a major clinical trial show.

Among over 5000 men aged 45-80 years randomized to daily transdermal testosterone gel or matching placebo gel for an average of 22 months, no increased risk was seen for a first occurrence of any component of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.

There was also no increased risk for prostate cancer over the 33-month follow-up period. However, there were increases in rates of atrial fibrillation, acute kidney injury, and pulmonary embolism in the testosterone group.

In terms of efficacy, testosterone therapy was associated with improved sexual function over 2 years of treatment and correction, or prevention, of anemia, but had no effect on progression to diabetes or glycemic parameters.

And an unexpected finding was a significant and unexplained 43% increase in fractures with testosterone therapy.

The TRAVERSE study was mandated by the US Food and Drug Administration in 2015 in response to concerns and conflicting data regarding the cardiovascular safety of testosterone replacement therapy in men. It was conducted by a consortium of five manufacturers of testosterone replacement products, led by AbbVie.

The results were presented June 17 during a symposium here at ENDO 2023: The Endocrine Society Annual Meeting. The mandated safety data were published online in the New England Journal of Medicine. The efficacy outcomes, undertaken opportunistically due to the trial's large sample size and relatively long follow-up, will be published later this year.

Taken together, the TRAVERSE findings are expected to transform the risk–benefit discussions with patients about the use of testosterone therapy for hypogonadism, study co-author Shalender Bhasin, MD, told Medscape Medical News.

"Testosterone deficiency doesn't kill people as far as we know but it is really an important symptomatic condition that affects quality of life. Many middle-aged and older men seek assistance for these symptoms, so it's an important condition and the treatment decisions are complicated," said Bhasin, who is director of the research program in men's health: aging and metabolism, at the Brigham and Women's Hospital in Boston, Massachusetts.

These new data will be incorporated into future guidelines on testosterone therapy in men with hypoandrogenism, noted Bhasin, a co-author of The Endocrine Society's 2018 guidelines.

"Findings Apply Only to Men With Bona Fide Testosterone Deficiency"

Asked to comment, endocrinologist Bradley D. Anawalt, MD, told Medscape Medical News that "the community of physicians who prescribe testosterone to men was waiting with bated breath" for the TRAVERSE results.

"Until now, we've had to say well, there might be a risk of strokes and heart attacks. This study does a lot to say that's not a serious risk, in the first few years anyway, of testosterone therapy. We still need long-term follow-up in these patients, or others, to see what the long-term risks are, but it's really reassuring," added Anawalt, who is professor of medicine at the University of Washington, Seattle.

Both Bhasin and Anawalt said the TRAVERSE trial in men is similar in many ways to the Women's Health Initiative (WHI). "[TRAVERSE] is not as big as [WHI], but it's framed in a similar way to ask those safety questions and to weigh the risk and benefit," Anawalt explained.

However, Anawalt stressed that the TRAVERSE safety data apply only to men with documented testosterone deficiency.

"It's important to emphasize that this is a study of men with bona fide testosterone deficiency and symptoms. It doesn't give carte blanche to prescribe to men with normal testosterone concentrations. It doesn't tell us about the safety of that," he noted.

Safety Reassuring, but Some Concerns Will Require More Investigation

TRAVERSE was a multicenter, randomized, double-blind, placebo-controlled noninferiority trial that enrolled 5246 men aged 45-80 years. Participants had pre-existing or were at high risk of cardiovascular disease, reported symptoms of hypogonadism, and had two fasting testosterone levels < 300 ng/dL. They were randomly assigned to receive daily transdermal 1.62% testosterone gel or placebo gel.

The primary safety endpoint event (first adjudicated major adverse cardiac event) occurred in 182 patients (7.0%) in the testosterone group and in 190 patients (7.3%) in the placebo group (hazard ratio, 0.96; P < .001 for noninferiority). Similar results were seen in sensitivity analyses.

Pulmonary embolism occurred in 0.9% of the testosterone group versus 0.5% of the placebo group, supporting current guidelines that testosterone should be used with caution in men who have had previous thromboembolic events, the authors note.

Prostate cancer occurred in 0.5% (n = 12) of patients in the testosterone group and 0.4% (n = 11) of patients in the placebo group, not a significant difference (P = .87).

There were, however, significant differences between the testosterone and placebo groups in terms of nonfatal arrhythmias warranting intervention (5.2% vs 3.3%; P = .001), atrial fibrillation (3.5% vs 2.4%; P = .02), and acute kidney injury (2.3% vs 1.5%; P = .04).

"These adverse events were not expected," the authors write.

Bhasin said that the team plans to investigate those cases further to look for possible risk factors, including whether COVID-19 played a role in these outcomes because the trial took place during the pandemic and some participants in both study groups contracted the virus.

Regarding acute kidney injury, Anawalt said: "I don't know that I believe that...It's probably a statistical abnormality. It barely made...significance."

Finally, "Real Data on Something We've Been Prescribing for Decades"

Both Bhasin and Anawalt pointed out the deficiencies in the prior literature in terms of what has been known about testosterone's effects. According to Bhasin, "In spite of all the folklore, there isn't very much known about the efficacy of treatment beyond sexual function, and even there, the data are really limited. Most trials have been open-label and very small."

He added that even among the few previous randomized clinical trials, only one, the so-called TTrials series, had an adequate number of participants and used robust measures to assess sexual function, but that study only lasted a year.

Indeed, Anawalt noted, "[TRAVERSE] and its father study, the TTrials, were the first systematic studies to look at large groups of men getting testosterone versus placebo. We're now starting to get real data on something that we've been prescribing for decades."

At the ENDO symposium, Bhasin presented data showing significant improvements with testosterone compared to placebo in overall sexual activity (P = .011), sexual symptoms (P < .001), and sexual desire over 1 year and maintained over 2 years in TRAVERSE. All were assessed using validated questionnaires.

"They confirmed that there's an improvement in sexual function and that it's sustained. That's important because there had been doubt about that...and it sounds like it's clinically significant," Anawalt commented.

Testosterone therapy was also associated with lower rates of anemia among men who were not anemic at baseline, and lower incidence of anemia in those who were anemic to begin with. However, the rate of progression from prediabetes to diabetes didn't differ significantly, nor did testosterone therapy improve glycemic control or remission in men who had diabetes at baseline, Bhasin reported.

"Big Surprise" and a Mystery: Testosterone Increased Fracture Risk

The fracture data were presented by Peter J. Snyder, MD, of the University of Pennsylvania, who earlier in the session had received an Endocrine Society award for his work in the testosterone field.

"No prior trial of testosterone treatment of hypogonadal men has been large enough or long enough to assess its effect on fractures...until the TRAVERSE trial," he said.

The hypothesis was that testosterone would decrease fracture incidence, as prior data had suggested it improves many parameters of bone quality in elderly men and in those with severe hypogonadism.

Instead, there were 91 confirmed and adjudicated clinical fractures in the testosterone group versus 64 in the placebo group, giving a hazard ratio of 1.43 (P = .03). The risk was seen across fracture types, increasing the likelihood that this finding was, in fact, real, Snyder said.

"We could speculate about a possible mechanism, but because we did not expect these results, we did not design the trial to evaluate a possible mechanism," Snyder noted.

Anawalt told Medscape Medical News that the fracture finding "was a big surprise. None of us would have expected that there would be an increase in fractures."

Clinically, Anawalt said it suggests consideration of expanding the use of antiosteoporotic medication such as bisphosphonates to men with low testosterone and elevated fracture risk for whom clinicians may have assumed that just giving them testosterone replacement might also protect their bones.

"This begs the question: Should we reorient the way we're thinking about these men?"

The study was funded by AbbVie, Acerus Pharmaceuticals Corporation/Aytu Biosciences, Allergan Sales, Endo Pharmaceuticals, and Upsher-Smith Laboratories. Bhasin has disclosed grants to his institution from Function Promoting Therapies and Metro International Biotech, and owns stock in XYone. Anawalt has reported no relevant financial relationships.

N Engl J Med. Published online June 16, 2023. Full text

ENDO 2023. Presented June 17, 2023.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.

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