Testing Testosterone: Two Studies Show Nothing to Promote Its Use Among Cardiovascular Patients

Decades after the first prescription of clinical testosterone—with scandal and sensation intermixed among the more appropriate reasons for its use—two new studies show somewhat conflicting evidence regarding how testosterone affects cardiovascular outcomes in men with androgen deficiency.

Prior research has linked testosterone therapy with increased cardiovascular events in high-risk men as well as venous thromboembolism within the first 6 months of treatment. Yet its use persists, particularly among men searching to look and feel younger.

“Who wouldn’t want to be young again? Obviously it’s an attempt to dial back the clock,” Sorin Brener, MD (New York Methodist Hospital, Brooklyn, NY), who was not involved in the studies, told TCTMD. There is “no question” that testosterone helps to reduce wrinkles, increase muscle mass, and improve healing ability, he said, but the question remains if there is a risk associated with using it, particularly in patients with preexisting coronary disease.

Who wouldn’t want to be young again? Obviously it’s an attempt to dial back the clock. Sorin Brener

For the first study, published Tuesday in JAMA, Peter Snyder, MD (University of Pennsylvania, Philadelphia), and colleagues used coronary CTA to measure the coronary plaque volumes of 138 men with low testosterone enrolled in the TTrials between 2010 and 2014. After adjusting for baseline plaque volume and other variables, the researchers found that those who used testosterone gel for 1 year were more likely to have a greater increase in coronary plaque levels compared with placebo (204 mm³ to 232 mm³ vs 317 mm³ to 325 mm³; P = 0.003) as well as greater median total plaque volume (272 mm³ to 318 mm³ vs 499 mm³ to 541mm³; P = 0.006).

In the second study, published Tuesday in JAMA: Internal Medicine, T. Craig Cheetham, PharmD, MS (Southern California Permanente Medical Group, Pasadena), and colleagues retrospectively looked at a cohort of more than 44,000 older men with androgen deficiency, 19.8% of whom who had ever been treated with testosterone. Over a median follow-up period of 3.4 years, men who had received testosterone were less likely than men who had never received it to report a composite of cardiovascular endpoints including acute MI, coronary revascularization, unstable angina, stroke, TIA, and sudden cardiac death (19.6 vs 23.9 events per 1,000 person years). The authors attempted to adjust for substantial differences in baseline characteristics between the study arms and found a lower risk of events remained for the men who had been treated with testosterone (adjusted HR 0.67; 95% CI 0.62-0.73).

Enough Evidence?

Brener deemed the studies, respectively, “mechanistic” and “administrative” in nature. “They are obviously in contradiction, but maybe as not as much as it appears,” he said. “The mechanistic study suggests that there is growth of plaque, but that doesn’t necessarily mean that there is actually a problem because the arteries can accommodate excess plaque.”

But given the lack of any randomized data and the “large” gap in baseline differences in the study by Cheetham et al, the issue of the appropriateness and safety of testosterone therapy in these men remains “unsettled,” according to Brener. “There is great concern that testosterone replacement therapy may not be good both because of the mechanistic study and the way that testosterone works. I don’t think the study from Kaiser really helps to alleviate that.”

An interesting finding from the Cheetham et al study, however, is that it “appears to be safe” to give testosterone to people with prior clinical cardiovascular disease, Brener said. “This is an important observation.”

In an editorial accompanying the studies as well as three others on the topic of testosterone use and various health outcomes, David Handelsman, MBBS, PhD (University of Sydney and Concord Hospital, Australia), said the current evidence points to “dimmed and disappointed if not yet finally dashed” hopes for testosterone treatment in older men.

“Overall, the findings from subtrials of the TTrials do not materially change the unfavorable balance of safety and efficacy to initiate testosterone treatment for age-related hypogonadism,” he writes. “For physicians prescribing off-label testosterone, these cardiovascular findings make it incumbent to strengthen warnings of adverse cardiovascular risk.”

Still, Handelsman acknowledges that “testosterone misuse will not simply disappear for lack of logic or evidence as none was needed to get it started,” and stresses the importance of education efforts from professional societies.

In his actual practice, however, Brener said he sees “very few” patients using testosterone. “It’s more of a curiosity than an actual acute problem that needs to be addressed,” he said.