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 wrote.
Dr. 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, Dr. 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 Dr. Bhasin and Dr. Anawalt pointed out the deficiencies in the prior literature in terms of what has been known about testosterone’s effects. According to Dr. 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 TTrials series, had an adequate number of participants and used robust measures to assess sexual function, but that study only lasted a year.
Indeed, Dr. 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, Dr. 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 one year, and maintained over two years in TRAVERSE. All were assessed by 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,” Dr. Anawalt said.
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, Dr. Bhasin reported.