Testosterone supplementation in men with low levels of the hormone did not increase the risk of heart attacks in a 5,246-patient study, allaying fears that were raised more than a decade ago in a smaller trial, researchers said Friday.
Although the results ease a significant safety concern about testosterone-containing gels and patches, the researchers running the study emphasized it does not address the more widespread use of such products in men who have normal levels of testosterone but who hope to avoid signs of aging or to increase virility.
The result is also an example of why advice on health topics can be so fraught, infuriating, and prone to change. Researchers frequently emphasize that the most reliable medical findings come from randomized trials, where patients are randomly assigned to either a treatment or a placebo. But the concerns about testosterone emerged from a 2010 study in 209 men that was stopped because men receiving the treatment appeared to be five times more likely to have heart attacks. Yet in a more rigorous and bigger study that finding completely disappeared.
Shalender Bhasin, one of the principal investigators of the new study and a professor at Harvard Medical School, called the results “very reassuring.” He had also been the lead investigator of the 2010 study that had flagged the risk.
In the new study, the data were “very conclusive,” he said, noting that the volunteers were at high cardiovascular risk. About 55% had a previous heart attack or stroke.
The study was published in the New England Journal of Medicine and is being simultaneously presented at the annual meeting of the Endocrine Society.
In the new study, called TRAVERSE, men whom blood tests had established to have low levels of testosterone were randomly assigned either to receive a testosterone gel or a placebo. Researchers tracked whether they died from cardiovascular causes, had a heart attack, or had a stroke, grouping those outcomes together in order to increase statistical power.
Cardiovascular death, heart attack, or stroke occurred in 182 patients, or 7%, in the testosterone group and in 190 patients, or 7.3%, in the placebo group. Statistically, this means that there was very little difference between the two groups – and that any risk to the heart for these patients is small.
One weakness of the study is that a fifth of patients dropped out, potentially in part because the trial was conducted during the pandemic. While that doesn’t appear to have affected the result, it is possible it could have.
Testosterone supplementation did have some apparent side effects. Arrythmias requiring medical intervention occurred in 5.5% of men in the testosterone group compared to 3.3% of those who received placebo, a difference that was highly statistically significant. There was also an imbalance in acute kidney injury, which occurred in 2.3% of patients in the drug group and 1.5% of those in the placebo group.
There was no difference in rate of benign prostate hyperplasia, and prostate cancer occurred in 12 patients in the testosterone group and 11 in the placebo group.
Efficacy results from the study on criteria such as anemia and sexual function will be presented at the Endocrine Society meeting but were not immediately available.
The authors cautioned that the result should not be used to justify widespread prescribing of testosterone. Bhasin, who is also a lead author of the Endocrine Society’s guidelines on treating low testosterone levels, said the condition occurs in about 3% of men aged 40 to 85. In the study, men had to have testosterone levels that were below a normal level of 300 nanograms per deciliter to participate. Blood tests were used to titrate how much testosterone they received, raising levels to between 350 ng/dL and 750 ng/dL. If levels went above that limit, the dose of testosterone was lowered.
“This was a specific group of men with a disease,” said Steven Nissen of the Cleveland Clinic, the chairman of the trial’s steering committee. “We do not want our study to be used as a justification for the widespread prescription of testosterone as a tonic for aging men so that they can try to feel like they were 18 to 25 years of age again. And I’m concerned that there will be misuse.
“I can see the ads now,” Nissen said.
It’s not clear why the smaller 2010 study produced such a different result. One difference, Bhasin said, was that although that study tracked cardiovascular events as a matter of course, they were not monitored carefully.
“It was not in our thinking at the time,” Bhasin said. “Nobody’s suspected that testosterone might increase or decrease the risk of cardiovascular events.”
It may also be that the earlier study was stopped too soon by the outside committee charged with monitoring patient safety when it saw an imbalance. In fact, all previous studies of testosterone combined had fewer heart attacks than TRAVERSE.
The earlier study led the Food and Drug Administration to instruct testosterone manufacturers to conduct a larger trial. The TRAVERSE study was funded by AbbVie, Acerus Pharmaceuticals, Endo Pharmaceuticals, and Upsher-Smith Laboratories, all of which are manufacturers of testosterone-containing products.