Jury Still Out on Cardiovascular Safety of Testosterone

Marlene Busko 

June 09, 2022

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 University, UK, and colleagues was published online June 8 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 US Food and Drug Administration (FDA) 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, 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 August 27, 2018, including 17 trials (3431 patients) for which the researchers obtained patient-level data. The individual trials were 3 to 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 [OR], 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, co-author of an accompanying editorial, told Medscape Medical News: "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"

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.

Nissen, a cardiologist at Cleveland Clinic, Ohio, 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," Michos noted.

"We should have more data soon" from TRAVERSE, said Michos, from the Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, 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 due to 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 Michos and fellow editorialist Matthew J. Budoff, MD, of UCLA, in their editorial.

Earlier Data Inconclusive

Testosterone concentrations progressively decline in men with advancing age, at about 2% per year, Michos and Budoff write. In addition, men with obesity or with diabetes have low levels of testosterone, Michos noted.

Low testosterone blood levels have been associated with insulin resistance, inflammation, dyslipidemia, and atherosclerosis. Testosterone replacement therapy has been used to increase libido, improve erectile dysfunction, and boost energy levels, mood, and muscle strength.

But it is well known that testosterone increases hematocrit, which has the potential to increase the risk of venous thromboembolism.

Two large observational studies have reported increased risks of myocardial infarction, stroke, and death in men taking testosterone, compared with nonusers, but the study designs have been widely criticized, Hudson and coauthors say in their article.  

A placebo-controlled trial was stopped early by its data and safety monitoring board following increased cardiovascular events in men aged 65 and older who received 6 months of testosterone. Other controlled trials have not observed these effects, but none was sufficiently powered.

Meta-Analysis Results

Hudson and colleagues performed a meta-analysis of 35 trials in 5601 men aged 18 years and older with low baseline testosterone (≤ 350 nmol/dL) who had been randomized to testosterone replacement therapy or placebo for at least 3 months, for which there were data on mortality, stroke, and cardiovascular outcomes.

The men were a mean age of 65, had a mean body mass index of 30 kg/m2, and most (88%) were White. A quarter had angina, 8% had a previous myocardial infarction, and 27% had diabetes. 

Cardiovascular and cerebrovascular outcomes were not primary outcomes.

During a mean follow-up of 9.5 months, in the 13 trials that provided this information, the rate of cardiovascular events was similar in the men who received testosterone (120/1601, 7.5%) compared to those who received placebo (110/1519, 7.2%).

In the 14 trials that provided this information, fewer deaths were reported during testosterone treatment (6/1621, 0.4%) than during placebo treatment (12/1537, 0.8%), but these numbers were too small to establish whether testosterone reduced mortality risk.

The most common cardiovascular events were arrhythmia, followed by coronary heart disease, heart failure, and myocardial infarction.

Patient age, baseline testosterone, smoking status, or diabetes status were not associated with cardiovascular risk.

The only detected adverse effects were edema and a modest lowering of HDL cholesterol.

"Men who develop sexual dysfunction, unexplained anemia, or osteoporosis should be tested for low testosterone," senior author of the meta-analysis Jayasena said in an email to Medscape Medical News.

However, Jayasena added, "Mass screening for testosterone has no benefit in asymptomatic men."

"Older men may still benefit from testosterone, but only if they have the clinical features [of hypogonadism] and low testosterone levels," he concluded.  

The current study is supported by the Health Technology Assessment program of the National Institute for Health Research. The TRAVERSE trial is sponsored by AbbVie. Jayasena has reported receiving research grants from LogixX Pharma. Hudson has reported no relevant financial relationships. Disclosures for the other authors are listed in the article. Michos has reported receiving support from the Amato Fund in Women's Cardiovascular Health at Johns Hopkins School of Medicine and serving on medical advisory boards for Novartis, Esperion, Amarin, and AstraZeneca outside the submitted work. Budoff has reported receiving grant support from General Electric.

Lancet Healthy Longev. 2022;3:E381-E393, E368-E369. Full text, Editorial

ENDO 2022. To be presented June 13, 2022. Abstract OR-25.

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