Despite a new meta-analysis claiming to show that testosterone replacement therapy for men with hypogonadism does not increase the risk of cardiovascular outcomes such as myocardial infarction or stroke, experts say the jury is still out.
A more definitive answer for cardiovascular safety of testosterone therapy will come from the TRAVERSE dedicated cardiovascular outcome trial, sponsored by AbbVie, which will have up to 5 years of follow-up, with results expected later this year.
The current meta-analysis by Jemma Hudson of Aberdeen (Scotland) University and colleagues was published online in The Lancet Healthy Longevity. The work will also be presented June 13 at ENDO 2022, the Endocrine Society’s annual meeting in Atlanta, Georgia, by senior author Channa Y. Jayasena, MD, PhD.
In 2014, the U.S. Food and Drug Administration mandated a label on testosterone products warning of possible increased cardiovascular risks and to reserve the therapy for symptomatic hypogonadism only. In contrast, the European Medicines Agency concluded that when hypogonadism is properly diagnosed and managed, there is currently no clear, consistent evidence that testosterone therapy causes increased cardiovascular risk.
To address this uncertainty, Dr. Hudson and colleagues formed a global collaborative to obtain individual patient data on cardiovascular outcomes from randomized controlled trials of testosterone therapy for men with hypogonadism.
They pooled data from 35 trials published from 1992 to Aug. 27, 2018, including 17 trials (3,431 patients) for which the researchers obtained patient-level data. The individual trials were 3-12 months long, except for one 3-year trial.
During a mean follow-up of 9.5 months, there was no significant increase in cardiovascular outcomes in men randomized to testosterone therapy versus placebo (odds ratio, 1.07; P = .62), nor were there any significantly increased risks of death, stroke, or different types of cardiovascular outcome, although those numbers were small.
This is “the most comprehensive study to date investigating the safety of testosterone treatment of hypogonadism,” according to the researchers. “The current results provide some reassurance about the short-term to medium-term safety of testosterone to treat male hypogonadism,” they conclude.
However, they also acknowledge that “long-term data are needed to fully evaluate the safety of testosterone.”
Erin D. Michos, MD, coauthor of an accompanying editorial, told this news organization, “This study doesn’t say to me that low testosterone necessarily needs to be treated. It’s still not indicated in people just for a low number [for blood testosterone] with less-severe symptoms. It really comes down to each individual person, how symptomatic they are, and their cardiovascular risk.”
‘Trial is not definitive’
Dr. Michos is not the only person to be skeptical. Together with Steven Nissen, MD, an investigator for the TRAVERSE trial, she agrees that this new evidence is not yet decisive, largely because the individual trials in the meta-analysis were short and not designed as cardiovascular outcome trials.
Dr. Nissen, a cardiologist at Cleveland Clinic, added that the individual trials were heterogeneous, with “very few real cardiovascular events,” so the meta-analysis “is not definitive,” he said in an interview.
While this meta-analysis “that pooled together a lot of smaller studies is reassuring that there’s no signal of harm, it’s really inconclusive because the follow-up was really short – a mean of only 9.5 months – and you really need a larger study with longer follow up to be more conclusive,” Dr. Michos noted.
“We should have more data soon” from TRAVERSE, said Dr. Michos, from the division of cardiology, Johns Hopkins University, Baltimore, who is not involved with that study.
Meanwhile, “I don’t think [this analysis] changes the current recommendations,” she said.
“We should continue to use caution as indicated by the FDA label and only use testosterone therapy selectively in people who have true symptoms of hypogonadism,” and be cautious about using it particularly in men at higher cardiovascular risk because of family history or known personal heart disease.
On the other hand, the meta-analysis did not show harm, she noted, “so we don’t necessarily need to pull patients off therapy if they are already taking it. But I wouldn’t right now just start new patients on it unless they had a strong indication.”
“Certainly, great caution is advised regarding the use of testosterone replacement therapy in people with established atherosclerosis due to the findings of plaque progression in the testosterone trials and the excess cardiovascular events observed in the TOM trial, write Dr. Michos and fellow editorialist Matthew J. Budoff, MD, of University of California, Los Angeles, in their editorial.