Injectable testosterone is associated with a higher short-term risk of cardiovascular events compared with testosterone gel or patch formulations, according to a new epidemiologic study of three large, diverse databases, which is the first research to compare cardiovascular events associated with different testosterone formulations.

The study is published online May 11 in JAMA Internal Medicine.

“There’s a large spike of serum testosterone that happens after an injection, so the injections may carry a slightly higher cardiovascular risk,” lead author Dr J Bradley Layton, from the University of North Carolina at Chapel Hill, told Medscape Medical News.

“The US Food and Drug Administration has just ruled that testosterone is really indicated and approved only for men with very specific endocrine disorders and not just general age-related decreases in testosterone,” he stressed.

Thus, clinicians considering starting a patient on testosterone should carefully consider the medical reasons for this therapy, he advised.
“With continuing concern about the safety and effectiveness of testosterone treatment in men with primary and age-related hypogonadism and the trend of treatment in men with normal testosterone levels or without recent baseline testing, it is important to understand the potential hazards of testosterone treatment,” he and his colleagues conclude.

And in an accompanying editorial, Dr Margaret E Wierman, from the Denver Veterans Affairs Medical Center, in Colorado, writes that the study findings support the Endocrine Society guidelines that recommend testosterone therapy purely for men who have hypogonadism as opposed to only low serum testosterone levels or related symptoms.

“The absolute risk [of cardiovascular events] between testosterone-therapy groups was small in this epidemiologic analysis, but the risk does raise concern, considering the marked increase in testosterone prescriptions both in the United States and internationally,” she adds.

More Than 500,000 Men in Three Cohorts

There have been mixed reports regarding adverse cardiovascular events with use of testosterone, Dr Layton and colleagues write.

Although it is known that testosterone injections cause spikes in serum testosterone levels, whereas transdermal patches and gels cause more subtle but sustained increases, until now, no studies have compared the cardiovascular safety of the different testosterone formats.
The researchers performed a retrospective cohort study in 544,115 men who had just been prescribed testosterone therapy after not having had any in the past 6 months.

The data came from three cohorts:

• 515,132 men in the United States with employer insurance (through Truven MarketScan) who made insurance claims for testosterone from 2000 through 2012.
• 22,376 men in the United States with Medicare insurance who made insurance claims for testosterone from 2007 through 2010.
• 6607 men in Great Britain who were seen by general practitioners and had healthcare claims for testosterone from 2000 until 2013,

The average age of men in the Medicare cohort was about 73, whereas the average age in the other two cohorts was about 54.

More men in the employer-insurance cohort received testosterone as a gel (56.5%), and the rest received an injection (36.7%) or, less often, a patch (6.8%). In the Medicare cohort, more men received an injection (51.2%), and the rest received a gel (42.9%), and again, less often, a patch (5.9%).

In the UK cohort, about the same percentage of men received a gel (42.4%) or an injection (39.6%), and a fair number received patches (18.1%).

Compared with men using testosterone gels, men receiving testosterone injections were more likely to have a cardiovascular event (myocardial infarction, stroke, or unstable angina), be hospitalized, or die within a year of starting treatment. Rates of venous thromboembolism did not differ between the formulations.

Risk of Outcome Within 1 Year, Testosterone Injection vs Gel

These risks were similar among users of testosterone gels and patches.

Risk of Outcome Within 1 Year, Testosterone Patch vs Gel

The 1-year rates of cardiovascular events and mortality were higher in the older Medicare cohort, and hospitalization rates were higher in the US cohorts.

Many Start Testosterone Without Testing

Many patients were started on testosterone without any record of serum testosterone test results or relevant diagnoses, but the researchers did not have complete data for this.

However, the findings are consistent with the “recent alarming US Food and Drug Administration report that more than 25% of testosterone prescriptions in the United States are written without determination of a [testosterone] level and that more than 30% of patients receiving testosterone therapy do not have follow-up laboratory testing,” Dr Wierman writes.

During the course of the study, the use of gels increased and use of the other formats decreased, which is “somewhat reassuring,” she adds.

The lack of evidence of a signal for venous thromboembolism was another important finding, and study strengths include the large number of men and patient and prescriber diversity.

The findings emphasize the need to prescribe testosterone only when warranted and to be aware of potential risks with certain formats and with values exceeding physiologic ones.

The study “can reassure physicians who rationally provide treatment for men with true hypogonadism with approaches that result in physiologic levels of testosterone, which is a safe and effective therapy,” according to Dr Wierman.

It also “[hints] that injectable Depo-Testosterone [testosterone cypionate, Pfizer] or other formulations that consistently result in levels outside the physiologic range should be restricted or at least more carefully monitored for cardiovascular risk.”