Testosterone therapy safe for the heart, but some experts disagree

Testosterone therapy appeared safe for the heart in men with hypogonadism, according to a meta-analysis of 35 placebo-controlled trials presented at ENDO 2022. However, experts have differing opinions on the findings.

There was no significant increase in CV events in men randomized to testosterone therapy compared with placebo (odds ratio [OR], 1.07; p=0.62), nor were there any significantly increased risks of death or stroke during a mean follow-up of 9.5 months, reported study investigator Dr Channa Jayasena from Imperial College London in London, UK. [ENDO 2022, abstract OR-25; Lancet Healthy Longev 2022;doi:10.1016/S2666-7568(22)00096-4]

There were fewer deaths with testosterone treatment than with placebo (0.4 percent vs 0.8 percent; odds ratio, 0.46; p=0.13 ), but the difference was not statistically significant.

“While there were a few deaths that happened so far, there’s no current evidence that testosterone would elevate CV or cerebrovascular risk,” Jayasena said.

The average age of patients in the trials was 65 years. The mean BMI was 30 kg/m².  At least 25 percent had angina, 8 percent had a history of myocardial infarction (MI), and 27 percent had diabetes. There was no evidence for treatment interaction by baseline CV status or age.

The meta-analysis was the most comprehensive of testosterone trials to date. “The findings provide some reassurance about the short-to-medium-term safety of testosterone therapy for male hypogonadism,” Jayasena said. “But data on long-term safety are needed.”

Too short follow-up period

“Although the current analysis is reassuring for safety, meta-analyses are only as good as the underlying data available,” commented Dr Erin Michos from Johns Hopkins University School of Medicine, Baltimore, Maryland, US, in an accompanying editorial. [Lancet Healthy Longev 2022;doi:10.1016/S2666-7568(22)00115-5]

She also considered as a limitation to the study the lack of data beyond 12 months. “The data are too insufficient to make conclusions on outcomes because the follow-up period [of 9.5 months] was too short,” Michos said. “I don’t think the finding changes the current recommendations.”

Caution warranted

Michos also urged caution when using testosterone replacement therapy particularly in men at higher CV risk, with a family history or known heart disease. She said caution is likewise recommended in people with established atherosclerosis owing to earlier findings that testosterone treatment was associated with increased coronary artery plaque volume in older men and an increased risk of CV adverse events. [JAMA 2017;317:708-716; N Engl J Med 2010; 363:109-122]

For men already on testosterone replacement therapy, “we don’t necessarily need to pull them off therapy,” Michos advised. “However, I wouldn’t start new patients on it unless they had a strong indication. At this stage, hormone therapy should still be used selectively, paying attention to the CV risk profile of individual patients.”

Dr Steven Nissen, a cardiologist at Cleveland Clinic in Ohio, US couldn’t agree more. He said the results are “not definitive” as the individual trials  – other than being short – were also not designed as cardiovascular outcome trials.  

Benefits and risks

The benefits of testosterone replacement therapy, for example, increased libido and energy level, and good effects on bone density, mood, and muscle strength, among others, have been well-documented. However, testosterone also increases haematocrit, which may increase the risk of venous thromboembolism in men of advancing age.

In the pooled data, the most common CV events in the testosterone and placebo groups were arrhythmia, coronary heart disease, heart failure, and MI. Oedema and erythrocytosis were more common in the testosterone group.

Testosterone significantly reduced serum total cholesterol, high-density lipoprotein (HDL), and triglycerides better than placebo. However, there were no significant differences in serum low-density lipoprotein (LDL), blood pressure, glycaemic parameters, diabetes incidence, and prostate adverse outcomes between groups. Although testosterone offered positive effects on quality of life and sexual function, the results varied.