Researchers have determined that testosterone supplementation in men with low levels of the hormone does not increase the risk of heart attacks, easing concerns raised more than 10 years ago after earlier findings.
While the small, 5 246-patient study allayed safety fears about testosterone-containing gels and patches, the researchers said it did not address the more widespread use of such products in men with normal levels of testosterone but who hope to avoid signs of ageing or to increase virility.
Researchers frequently reiterate that the most reliable findings come from randomised 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 likelier to have heart attacks.
Yet in a more rigorous and bigger study that finding completely disappeared, reports Stat News.
Shalender Bhasin, one of the principal investigators of the new study and a professor at Harvard Medical School, called the results “very reassuring”. He was also the lead investigator of the 2010 study that had flagged the risk.
In the latest 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 new data were “very conclusive,” he said, noting that the volunteers were at high cardiovascular risk. About 55% had had a previous heart attack or stroke.
A weakness of the research, however, was 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 with 3.3% of those receiving 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.
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.
For the study, men were required to have testosterone levels below a normal level of 300 nanograms per decilitre 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 testosterone dose 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 ageing men so that they can try to feel as if they are 18 again. And I’m concerned there will be misuse.”
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 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 US Food and Drug Administration to instruct testosterone manufacturers to conduct a larger trial.
Study details
Cardiovascular Safety of Testosterone-Replacement Therapy
Michael Lincoff, Shalender Bhasin, Panagiotis Flevaris, Lisa Mitchell, Shehzad Basaria, William Boden, Glenn Cunningham, Christopher Granger, Mohit Khera, Ian Thompson, Qiuqing Wang, Kathy Wolski, et al.
Published in New England Journal of Medicine on 16 June 2023
Abstract
Background
The cardiovascular safety of testosterone-replacement therapy in middle-aged and older men with hypogonadism has not been determined.
Methods
In a multicentre, randomised, double-blind, placebo-controlled, non-inferiority trial, we enrolled 5246 men 45 to 80 years of age who had pre-existing or a high risk of cardiovascular disease and who reported symptoms of hypogonadism and had two fasting testosterone levels of less than 300 ng per decilitre. Patients were randomly assigned to receive daily transdermal 1.62% testosterone gel (dose adjusted to maintain testosterone levels between 350 and 750 ng per decilitre) or placebo gel. The primary cardiovascular safety end point was the first occurrence of any component of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, assessed in a time-to-event analysis. A secondary cardiovascular end point was the first occurrence of any component of the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization, assessed in a time-to-event analysis. Non-inferiority required an upper limit of less than 1.5 for the 95% confidence interval of the hazard ratio among patients receiving at least one dose of testosterone or placebo.
Results
The mean (±SD) duration of treatment was 21.7±14.1 months, and the mean follow-up was 33.0±12.1 months. A primary cardiovascular end-point 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; 95% confidence interval, 0.78 to 1.17; P<0.001 for non-inferiority). Similar findings were observed in sensitivity analyses in which data on events were censored at various times after discontinuation of testosterone or placebo. The incidence of secondary end-point events or of each of the events of the composite primary cardiovascular end point appeared to be similar in the two groups. A higher incidence of atrial fibrillation, of acute kidney injury, and of pulmonary embolism was observed in the testosterone group.
Conclusions
In men with hypogonadism and pre-existing or a high risk of cardiovascular disease, testosterone-replacement therapy was non-inferior to placebo with respect to the incidence of major adverse cardiac events.
See more from MedicalBrief archives:
Endocrine Society updates testosterone treatment guidelines
Testosterone Tx improves bone density and anaemia, but with heart risk
No link between testosterone therapy and cardiac risk
Testosterone therapy ‘doesn’t increase heart attack risk’